Life Long Learning in Neurology - part 2 pptx

17 asymptomatic mutation-positive patients is not known. Without clinical and genetic evaluation, it cannot be known if the sister has inherited the affected gene. Although the onset is usually in the second decade of life, phenotypes vary. 17. A 10-year-old boy presents with a 1-year history of difficulties in school, behavioral problems, and unsteady gait. He was the product of a normal gestation and delivery and reached his early milestones at the appropriate time. Over the last year he has become more withdrawn and has failed several of his classes at school. Previously he was a good student. He has been previously healthy and takes no medications. Family history reveals that his father had some form of a progressive mental illness with "shaking" and committed suicide at age 42. Numerous relatives on his paternal side were institutionalized in middle age for "mental disease," several of whom died of suicide. There is no maternal family history of neurological or psychiatric illness. On examination, he is distractible and scores 20/30 on the Mini-Mental Status Examination. He has a masked face and reduced eye blink. His gait is bradykinetic. There is diffuse rigidity in the axial musculature and extremities. He has diffuse hyperreflexia and bilateral Babinski signs. MRI of the head is normal. Genetic testing reveals 110 CAG repeats in a gene on 4p16.3. In addition to demonstrating anticipation, the inheritance of this patient's disease is also an example of which of the following? A. Autosomal recessive inheritance B. Probable nonpaternity C. Parent-of-origin effect D. Expansion of a gene in a noncoding region E. X-linked dominant inheritance Correct Answer: The correct answer is C. This patient has the juvenile Westphal variant of Huntington's disease (HD). This disorder results from increased numbers of CAG repeats (coding for glutamine) in the coding region of a gene on 4p16.3, coding for the huntingtin protein. The larger the repeat expansion, the earlier and more severe the disease. With progressive generations, the repeat expansion often enlarges (anticipation). When the disease onset is in childhood, the gene has almost always been inherited from the father (parent-of-origin effect). This should not be a case of nonpaternity as the father's "mental illness" and that of numerous paternal family members were almost certainly HD. HD is inherited in an autosomal dominant pattern. 18. A 44-year-old man presents with a 4-year history of progressive gait difficulties. In recent months he has noted difficulty with upper extremity incoordination. He reports occasional episodes of horizontal diplopia and notes difficulty looking up into the rearview mirror when driving. His 65-year-old father has been in a nursing home for 10 years with ataxia and some form of peripheral neuropathy. On examination, he has prominent lid retraction with mild exophthalmos. Impaired voluntary vertical and horizontal gaze is present, but the oculocephalic reflex is intact. He has an ataxic dysarthria. Mild tongue wasting and weakness with fasciculation are present. His limb strength is 5/5 diffusely. The deep tendon reflexes are symmetrically brisk, and the plantar reflexes are flexor. His gait is broadbased and ataxic. Moderate limb ataxia is present. The remainder of his examination is normal. Which of the following disorders is the most likely diagnosis in this patient? A. Dentatorubral-pallidoluysian atrophy B. Machado-Joseph disease C. Friedreich ataxia D. Spinocerebellar ataxia type 10 E. Ataxia telangiectasia Correct Answer: The correct answer is B. This patient has a cerebellar ataxia with onset in middle age. Associated symptoms include supranuclear ophthalmoplegia, lid retraction, and tongue fasciculations. The most likely diagnosis is spinocerebellar ataxia type 3 (Machado-Joseph disease). This disorder is caused by an autosomal dominant polyglutamine-coding CAG repeat expansion on chromosome 14. The age of onset depends on the repeat length. Longer repeats present earlier with dystonia and pyramidal signs. Intermediate-length repeats present in middle age with ataxia, and shorter repeats present in older patients with amyotrophy/neuropathy. Exophthalmos is characteristic, although not always present. Dentatorubral-pallidoluysian atrophy is a rare progressive ataxia with cognitive changes, chorea, and seizures. Friedreich ataxia and ataxia telangiectasia are autosomal recessive ataxias with onset in childhood. Spinocerebellar ataxia type 10 is an ataxic syndrome with seizures primarily seen in families of Mexican descent. 19. A 13-year-old boy presents with a 1-year history of progressive ataxia and upper extremity incoordination. He is a good student but has not been able to participate in sports this school year because of difficulty running. Recently his parents have noted that his speech is slurred. On examination, he has high arches and a mild thoracic scoliosis. He has a mild ataxic dysarthria. Ataxic visual pursuit and nystagmus are present. The funduscopic examination is normal. His strength is 5/5 throughout. The deep tendon reflexes are symmetrically reduced. Babinski sign is present bilaterally. Reduced vibration and joint position sense are present in the feet. Testing for 18 metabolic disorders is negative. MRI of the head shows cerebellar atrophy. Genetic testing reveals a large repeat GAA expansion (500 repeats) of the FRDA gene on chromosome 9q. Which of the following additional tests would be most appropriate in this patient? A. Serum immunoglobulins B. Serum [alpha]-fetoprotein C. Echocardiogram D. Blood smear for acanthocytes E. Ceruloplasmin level Correct Answer: The correct answer is C. This patient has Friedreich ataxia, an autosomal recessive GAA repeat expansion disorder of the FRDA gene on chromosome 9q. Hypertrophic cardiomyopathy is common in these patients. Arrhythmias and cardiac failure are a major cause of morbidity and mortality. Immunoglobulin deficiency and elevated a-fetoprotein levels are seen in ataxia telangiectasia. Acanthocytosis is a feature of abetalipoproteinemia. Low ceruloplasmin levels are seen in Wilson's disease, an autosomal recessive disorder due to a gene defect on chromosome 13. 20. A 5-year-old boy presents with developmental delay and a 3-month history of generalized tonic-clonic seizures. Examination shows facial angiofibromas and hypomelanotic skin macules. Which of the following is the most likely diagnosis? A. Lafora disease B. Unverricht-Lundborg disease C. Severe myoclonic epilepsy of infancy D. Tuberous sclerosis E. Myoclonic epilepsy with ragged red fibers Correct Answer: The correct answer is D. Facial angiofibromas and hypomelanotic skinC macules are common examination findings in tuberous sclerosis; this patient's seizures most likely represent secondary generalization from a focal cortical hamartoma. Severe myoclonic epilepsy of childhood presents as intractable epilepsy within the first year of life with developmental delay. Lafora disease and Unverricht-Lundborg disease present as progressive myoclonic epilepsy with intellectual deterioration, and myoclonic epilepsy with ragged red fibers is characterized by myoclonic epilepsy and myopathy. None of these other conditions is associated with the dermatological findings seen in this patient. 21. A 12-year-old boy is brought to the office by his mother because she is concerned about his risk of developing Huntington's disease (HD). The boy has no neurological or psychiatric symptoms or signs and is doing well in school. His 36-year-old father was diagnosed with HD 2 years ago. Which of the following is the most accurate statement regarding HD gene testing in this patient? A. Testing for the HD gene in the child should proceed as long as written consent is obtained from both parents. B. Testing for the HD gene in this child should proceed with consent of the parents only if the child appears to fully understand the ramifications of the test. C. Testing for the HD gene should occur only if formal neuropsychological testing reveals an abnormality. D. Testing for the HD gene in this child is not appropriate because no effective preventive treatment of this disease is currently available. E. Testing for the HD gene in this child is not appropriate because this test is usually not accurately predictive of the development of disease. Correct Answer: The correct answer is D. Whether or not consent is obtained from the family or the patient appears to understand the significance of the test, presymptomatic testing in a minor is not appropriate for HD or any other disease for which no preventive intervention is currently available. Likewise, performing neuropsychological testing to screen for a previously unrecognized problem is not appropriate in this scenario. Although some HD gene testing may result in the finding of intermediate repeat lengths and an indeterminant risk of disease, the finding of a clearly abnormal CAG repeat length (ie, greater than 40) is accurately predictive of the development of HD. Testing in a minor should only occur if the patient is symptomatic (ie, as a diagnostic, but not a predictive, test). The potential for psychosocial harm (regarding employment, insurance, or personal interactions) as a result of predictive testing is particularly great for a minor, and at least 90% of those at risk choose not to undergo predictive testing once they reach adulthood. 22. A 17-year-old boy presents with a 4-year history of generalized tonic-clonic seizures associated with intermittent myoclonic jerks of the upper extremities. The seizures have been refractory to antiepileptic drugs. His cognitive function has undergone a gradually progressive decline. EEG shows spike-and-wave discharges of 3-Hz frequency. Which of the following diagnostic tests is most likely to establish the diagnosis? A. Brain MRI B. Genetic testing 19 C. Neuropsychological testing D. Repeat EEG E. Magnetic source imaging Correct Answer: The correct answer is B. This patient's clinical history is most consistent with a syndrome of progressive myoclonic epilepsy. However, no additional information is available to identify the underlying cause. For such difficult cases, genetic testing is now available for Lafora disease, Unverricht-Lundborg disease, and myoclonic epilepsy with ragged red fibers. Brain MRI is likely to be unremarkable in each of these conditions, and neuropsychological testing would not specifically differentiate between the causes of progressive myoclonic epilepsy. Further EEGs in this patient would not be diagnostically useful since an EEG abnormality consistent with progressive myoclonic epilepsy has already been found in this patient. Magnetic source imaging is not indicated in this case. This study is most useful when lateralizing clinical features or interictal spike discharges suggest the presence of a resectable epileptogenic focus. 23. A 3-year-old boy presents with severe motor developmental delay. He was the product of a normal pregnancy and vaginal delivery. Postpartum he was noted to have reduced muscle tone. He has had numerous respiratory illnesses, some requiring hospitalization but none requiring artificial ventilation. He was able to sit unsupported at 10 months and crawl at 11 months. He began to walk at age 2 but has required leg and ankle bracing. Bowel and bladder function are normal, and cognitive development has been normal. There is no family history of neuropathy, and the patient has two older siblings who are neurologically normal. Motor testing reveals severe distal weakness in the upper and lower extremities with marked distal wasting. Pes cavus and scoliosis are present. The deep tendon reflexes are absent. There is a stocking-glove loss to all sensory modalities. Spirometry reveals evidence of respiratory muscle weakness. Nerve conduction studies show reduction of sensory and motor amplitudes and markedly slowed conduction velocities (in the range of 10 m/s). A sural nerve biopsy shows evidence of severe demyelination and axonal loss. Which of the following is the most accurate statement concerning this patient's condition? A. Insufficient data are available to diagnose Dejerine-Sottas neuropathy in this patient. B. The absence of a family history makes an inherited neuropathy unlikely. C. The sural nerve biopsy was an essential part of the patient's evaluation. D. Genetic testing should include a search for missense mutations in PMP and EGR2. E. Any male siblings of the patient will be at no risk to develop this problem. Correct Answer: The correct answer is D. This patient meets the clinical criteria for Dejerine-Sottas neuropathy, which include onset by 2 years of age; severe motor, sensory, and skeletal deficits; markedly abnormal nerve conduction velocities, and evidence of severe demyelination or axonal loss on nerve biopsy. It is a clinical designation and includes multiple disorders associated with mutations or deletion of PMP22, MPZ, EGR2, among others. The absence of family history does not exclude an inherited neuropathy as the disorder may be autosomal recessive or represent a new mutation. False paternity is also a possibility. Sural nerve biopsies are rarely necessary to make a diagnosis in patients with a Dejerine-Sottas phenotype or to define the genetic cause. Risk to any other future children the parents may have cannot be determined until the mutation and pattern of inheritance are established. This underscores the importance of genetic testing. 24. A woman has two sons who were diagnosed with Duchenne muscular dystrophy in early childhood, both of whom were found to have a deletion of exons 40 through 52 of the dystrophin gene. The woman herself does not have a dystrophin deletion, however. Which of the following genetic processes is the most likely explanation for this woman's normal testing? A. Anticipation B. Germline mosaicism C. Mitochondrial inheritance D. New mutation E. Paternal inheritance Correct Answer: The correct answer is B. This woman is most likely germline mosaic for the dystrophin deletion, ie, her blood DNA is normal, but her germline carries the mutation that was passed on to her affected sons. Mitochondrial inheritance (which is always maternally transmitted) is an implausible explanation since the dystrophin gene is on the X chromosome. Paternal inheritance cannot be an explanation since the gene on the X chromosome can only be passed from the mother to the children. Since the genetic abnormality here is not a trinucleotide repeat, anticipation would not explain the patient's normal testing; anticipation refers to the phenomenon seen in some trinucleotide repeat diseases where abnormal expanded repeats may become larger from generation to generation, causing earlier symptom onset and more severe disease in successive generations. 25. A 4-year-old boy presents with a 12-month history of weakness and falls. His parents note that he seems clumsy, has difficulty running and climbing stairs, and tends to walk on his toes. He has a 6-year-old brother and a 20 12-year-old sister who are well, and there is no other family history ofsimilar difficulties. Examination shows mild weakness in deltoids and hip flexors, and hypertrophy of the calves. Sensation appears normal, and reflexes are 1+ and symmetrical, with downgoing toes. Gowers' sign is present. His gait is waddling, and he tends to walk on his toes. Serum CK is 8784 IU/L. Which of the following is the most appropriate next step in diagnostic evaluation? A. DNA testing B. Electromyography C. MRI of the brain D. Muscle biopsy E. Skin biopsy Correct Answer: The correct answer is A. This patient's signs, symptoms, and CK elevation are typical of Duchenne muscular dystrophy, which is due to a mutation in the dystrophin gene. Routine DNA analysis of the dystrophin gene identifies 60% to 70% of dystrophin mutations (deletions and duplications). If DNA testing for a dystrophin mutation in this patient is normal, then the next step would be to perform a muscle biopsy with dystrophin immunohistochemistry. Electromyography would not likely add further diagnostic specificity in this child whose signs and symptoms already are most consistent with a dystrophic muscle process. MRI of the brain and skin biopsy (for merosin immunostaining) can be helpful in the evaluation of patients with congenital muscular dystrophy but are not indicated in this scenario. 26. An 8-year-old girl presents because of weakness. Her parents note that she seems to have been weaker than other children since birth and she was never able to run or jump like others her age. No definite worsening has occurred. Her family history is notable for a paternal aunt who died at age 18 of malignant hyperthermia during general anesthesia for an appendectomy; she had no history of weakness. Examination shows 4/5 strength in hip flexors and deltoids; the remainder of the motor examination is normal. Sensation is normal, and reflexes are 2+ and symmetrical with downgoing toes. Serum CK is 184 IU/L. Which of the following is the most likely diagnosis? A. Central core disease B. Duchenne muscular dystrophy C. Limb-girdle muscular dystrophy D. Myofibrillar myopathy E. Nemaline myopathy Correct Answer: The correct answer is A. This patient's clinical history and examination are most consistent with a congenital myopathy. Central core disease, an autosomal dominant congenital myopathy, is associated with susceptibility to malignant hyperthermia under certain forms of general anesthesia and is, therefore, the most likely diagnosis. Susceptibility to malignant hyperthermia can occur in patients with central core disease even if they do not have clinical weakness. Myofibrillar myopathy and nemaline myopathy are also forms of congenital myopathy but are not associated with malignant hyperthermia. Duchenne muscular dystrophy is unlikely given the patient's sex and the normal CK; limb-girdle muscular dystrophy is also unlikely because of the normal CK. In addition, neither of these conditions is associated with susceptibility to malignant hyperthermia. 27. A 30-year-old man presents with a 2-year history of progressive gait and limb ataxia, dysarthria, and spasticity in all four limbs. There is no family history of ataxia or other neurological diseases. The workup for metabolic and paraneoplastic disorders is negative, and MRI of the head demonstrates only cerebellar and brain stem atrophy. Despite the negative family history, this patient could still have an inherited form of ataxia for which of the following reasons? A. Autosomal recessive inheritance pattern B. Incomplete penetrance of the mutation in other family members C. Death of carrier parent before symptom onset D. New mutation in the proband E. All of the above are correct Correct Answer: The correct answer is E. Patients with autosomal recessive ataxias are often the only affected person in their family, particularly if the proband has few siblings. In autosomal dominant ataxias, one can have an apparently negative family history due to incomplete penetrance of the mutation, early death of the carrier parent before symptom onset, false paternity, or the occurrence of a de novo mutation in the proband. An X-linked pattern of inheritance can also be missed if there are few maternal male relatives, and mitochondrial diseases can be sporadic. 28. A 20-year-old woman presents with a 5-year history of migraine headaches. More recently, she has developed vertigo, dysarthria, and unsteady gait with her migraines. These episodes last several hours and then resolve. They tend to occur during times of stress and after intense exercise. In the last few months she has noted mildly impaired balance, which makes running on a treadmill difficult. Her father had episodes of ataxia before his death of heart attack at age 40. She is an only child and has no other affected relatives. Her neurological examination is entirely 21 normal save for mild difficulty with tandem gait. Neuroimaging and metabolic workup for cerebellar ataxia are negative. Genetic testing for repeat expansion ataxic disorders is negative. Which of the following medications is most likely to be helpful in treating and preventing this patient's episodes? A. Vitamin E B. Calcium carbonate C. Acetazolamide D. Idebenone E. Propranolo Correct Answer: The correct answer is C. This patient most probably has episodic ataxia type 2, an autosomal dominant disorder due to a mutation in a gene (CACNA1A) coding for a calcium channel protein. Commercial genetic testing is not yet available for this disorder. Acetazolamide may be very helpful as symptomatic treatment for this disorder. The other medications listed would not be helpful for this disorder. 29. A 15-year-old boy presents with a 3-year history of progressive weakness. He has no other significant past medical history. Family history is significant for a brother who also had weakness and died of sudden cardiac death at the age of 16. There is no history of weakness, syncope, or cardiac problems in his 22-year-old brother, his 10- and 18-year-old sisters, or his parents. Examination shows contractures of his elbows and ankles, with 4/5 weakness in biceps, triceps, and tibialis anterior muscles. Sensation is normal, and reflexes are 1+ and symmetrical with downgoing toes. Serum CK is 320 IU/L. Mutations of a gene encoding which of the following proteins is most likely responsible for this patient's illness? A. Myotubularin B. Dystrophin C. Emerin D. Fukutin-related protein E. Merosin Correct Answer: The correct answer is C. This patient's signs and symptoms are most consistent with X-linked Emery-Dreifuss muscular dystrophy (EDMD), which is caused by mutations in emerin, a widely expressed protein. EDMD is characterized by early contractures, progressive limb-girdle weakness, and cardiomyopathy, which may present as a life-threatening rhythm disturbance. A phenotypically identical but autosomal dominant form of EDMD is caused by mutations in another nuclear lamina protein, lamin A/C. Mutations in dystrophin are associated with Duchenne-Becker muscular dystrophy, which is less likely than EDMD in this patient, especially given this patient's early contractures and the very mildly elevated CK. Mutations in merosin and fukutin-related protein are implicated in certain forms of congenital muscular dystrophies not suggested by this patient's clinical history. Mutations in fukutin-related protein are also associated with some of the later-onset limb-girdle muscular dystrophies, but this diagnosis is also less consistent with this patient's history and examination than EDMD. Mutations of myotubularin are seen in myotubular myopathy, an X-linked congenital myopathy that usually presents in infancy with profound hypotonia and respiratory insufficiency. 30. An 8-year-old boy presents with a 6-month history of gait problems and learning difficulties. He was the product of a normal gestation and delivery. He reached the usual childhood milestones at the appropriate time and has been a good student in school. This semester, however, he has had behavioral problems and has obtained poor grades. His parents note that he is clumsier and falls frequently when playing with his friends. He has two healthy sisters. His mother is adopted and has no knowledge of her biological family. There is no family history of neurological disorders in his father or his father's family. On examination, the patient is noted to have increased pigmentation of the oral mucosa and skin folds. He is highly distractible and hyperactive. The cranial nerve examination reveals mild optic atrophy. Hearing is reduced. His gait is slightly stiff, broad based, and ataxic. Strength is 5/5 throughout. The deep tendon reflexes are symmetrically increased, and Babinski sign is present bilaterally. The sensory examination is normal. MRI of the head reveals increased T2 signal in the parieto-occipital regions bilaterally without contrast or mass effect. Pontocerebellar atrophy is present. Plasma very long chain fatty acids are increased, and serum cortisol is reduced. Which of the following is the most accurate statement concerning this patient's neurological disorder? A. There is a 50% risk that any future male siblings of this patient will be affected. B. Dietary therapy is effective in reversing neurological deficits in this condition. C. This disorder is associated with a mutation in mitochondrial DNA. D. Steroid replacement will reduce neurological disability. E. The absence of other affected family members suggests false paternity. Correct Answer: The correct answer is A. This patient has adrenoleukodystrophy, which is due to a mutation in the X-ALD gene on chromosome Xq28. As the disorder is X-linked, the gene affects male offspring of female carriers. As the disorder is maternally transmitted, the father's side of the family would not have a history of the disorder. 22 Fifty percent of male offspring of female carriers will inherit the mutation. However, because of the broad phenotypical heterogeneity of the disorder, only about half will develop the illness. Dietary therapy has little effect on either the progression or preexisting neurological deficits in affected patients. Corticosteroid replacement therapy may be necessary for other reasons but does not affect neurological disability. 31. An 8-year-old boy presents with seizures and mental retardation since infancy. He was the product of a normal birth and gestation. He was slow to reach developmental milestones and is able to attend school in special education classes. He began having infantile spasms at age 6 months but now has generalized tonic-clonic seizures about once a month. There is no family history of neurological disease. On physical examination he has a nodular malar rash. Periungual fibromas are present, and a few hypopigmented macules are on the skin of his back when viewed with a Wood's lamp. No focal abnormalities are found on neurological examination. Computed tomography and MRI of the head demonstrate multiple, calcified, and minimally enhancing lesions in the subependymal regions. Genetic testing reveals a mutation in the TSC1 gene on chromosome 9q. Genetic testing of the parents is negative for the mutation. Which of the following is the most appropriate counseling to the parents of this child? A. The parents have a 50% chance of having another affected child B. The absence of genetic abnormality in the parents is most suggestive of false paternity C. The patient is at increased risk of developing astrocytoma D. The patient's future offspring will have a 25% chance of being affected by this disorder E. Other than the skin and nervous system, major organ systems are not affected by this disorder Correct Answer: The correct answer is C. This patient has tuberous sclerosis, a genetic disorder inherited as an autosomal dominant trait. Mutations are possible in two genes: TSC1 (chromosome 9) and TSC2 (chromosome 16). Two thirds of patients have sporadic de novo mutations; thus there is no family history. Affected individuals who reproduce have a 50% chance of having an affected offspring. There is at least a 5% chance of development of astrocytoma. Subependymal giant cell astrocytomas are most common. In addition to the skin and nervous system, rhabdomyomas are seen in the heart, and angiomyolipomas may be seen in the kidneys of these patients. 32. A 6-year-old girl presents with a 6-month history of unsteady gait and frequent falls. Over the same time frame she has developed tremor of the head and upper extremities. She was the product of a normal gestation and delivery, and her development up to this point has been normal. There is no family history of ataxia or other neurological disease. On examination, her cognitive function is normal. She has mild dysarthria. The funduscopic examination reveals pigmentary changes in the retina but no evidence of optic atrophy. There is titubation of the head. Strength is 5/5 throughout, and deep tendon reflexes are symmetrically reduced. The plantar responses are flexor. Vibration and joint position sense are reduced in the hands and feet. Her gait is broad based and ataxic. Romberg's sign is positive. Laboratory testing reveals very low serum vitamin E levels. Vitamin A and D levels are normal. Which of the following is the most likely cause for this patient's signs and symptoms? A. Gastrointestinal malabsorption disorder B. Malnutrition C. Friedreich ataxia D. Mutation in [alpha]-TTP gene E. Ataxia telangiectasia Correct Answer: The correct answer is D. This patient has a spinocerebellar ataxia due to the vitamin E deficiency. The fact that her vitamin A and D levels are normal suggests the cause is unlikely to be due to dietary deficiency or malabsorption. Although many of the clinical features are similar to those of Friedreich ataxia and ataxia telangiectasia, the very low vitamin E level makes this possibility less likely. She most probably has ataxia with isolated vitamin E deficiency, an autosomal recessive disorder due to frame-shift mutations in the gene coding for the [alpha]-tocopherol transfer protein ([alpha]-TTP). Deficiency in this protein causes vitamin E deficiency due to inadequate recycling of vitamin E. Oral vitamin E supplementation may produce clinical improvement or at least retard progression. 33. A 30-year-old woman presents to her physician with a 2-year history of paresthesias and sensory loss in her palms and soles. Over the last year, she has noted weakness in her ankles and a tendency of her toes to trip her when ascending stairs. She reports that she has always had high arches and difficulty wearing high heels. She had no difficulty keeping up athletically in school but reports a relatively sedentary lifestyle for the past 10 years. Her 25-year-old brother has high arches and reports some difficulties with his feet. The patient's 55-year-old mother has had "foot problems" for many years and has worn bilateral ankle-foot orthotics for the last 10 years. The patient's maternal grandmother and a maternal uncle may have had similar symptoms, but both died in their 60s of heart disease. No other family members have symptoms of neuropathy. On examination, she has high arches and atrophy of the intrinsic muscles of the hands and feet. She has a mild steppage gait and particular difficulty walking on her heels. There is symmetrical 4/5 weakness of muscles of the distal upper and lower extremities but proximal strength is 5/5. Deep tendon reflexes are absent at the ankle and symmetrically reduced at the knee and elbow. The 23 plantar responses are flexor. Sensory examination reveals reduction to all modalities in a stocking-glove distribution. The remainder of the neurological examination is normal. Nerve conduction studies reveal slowing of motor and sensory conduction velocities in the 36 m/s range. Based on this patient's family history, which of the following genetic abnormalities is most likely to be present? A. Mutation in the GJB1 gene B. Duplication in the PMP22 gene C. Deletion in the GARS gene D. Mutation in the senataxin gene E. Mutation in the SPTLC1 gene Correct Answer: The correct answer is A. The pattern of inheritance suggests an X-linked dominant condition (no male-to-male inheritance), although an autosomal dominant condition remains a possibility. The X-linked form of CMT, CMTX, is due to a point mutation in the GJB1 gene that codes for the connexin 32 gap junction channel protein, which is expressed in the Schwann cell. Occasionally women can be affected, although typically the men in a family are more significantly affected. Duplication in the PMP22 gene produces CMT1A, an autosomal dominant disorder that usually produces more severe slowing of nerve conduction velocities (in the range of 20 m/s). Mutations in the GARS gene produce an autosomal dominant axonal neuropathy (CMT2D) or a motor neuropathy, hereditary motor neuropathy type V. Mutations in the senataxin gene produce an autosomal dominant disorder with both upper and lower motor neuron abnormalities and normal sensory examination (ALS4). Patients with point mutations in the SPTLC1 gene have hereditary sensory and autonomic neuropathy and develop difficulties primarily in small fiber nerve function. Nerve conduction velocities are usually normal. 34. A 22-year-old woman presents with a 3-year history of progressive ptosis and diplopia. She carries a diagnosis of "seronegative ocular myasthenia gravis" but has never responded to pyridostigmine or corticosteroids. She has had reduced hearing bilaterally since her early teens and was recently noted to have second-degree heart block when she had a syncopal spell. For the last 6 months she notes unsteady gait. There is no family history of neurological disease of any sort. On examination, she is of short stature. Mental status is normal. Her cranial nerve examination reveals bilateral severe ptosis and complete ophthalmoplegia. Mild pigmentary changes are noted in the retinas. Bilateral sensorineural hearing loss is present. She has mild to moderate proximal weakness in the arms and legs. The deep tendon reflexes are normal. Her gait is broad based and ataxic. She cannot tandem walk without falling. Finger-nose and heel-shin testing reveal mild limb ataxia. MRI of the head with contrast reveals mild cerebellar atrophy. Serum lactate is elevated. Which of the following is the most likely diagnosis? A. Myoclonic epilepsy with ragged red fibers B. Mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes (MELAS) C. Kearns-Sayre syndrome D. Leigh disease E. Oculopharyngeal muscular dystrophy Correct Answer: The correct answer is C. This patient has chronic progressive external ophthalmoplegia, also known as Kearns-Sayre syndrome (KSS). KSS results from a deletion in mitochondrial DNA. Spontaneous (ie, not maternally inherited) mutations are present in about 80% of patients. Therefore, there is often no family history of the disorder. The presence of ophthalmoplegia and ptosis is unique to KSS, which lacks seizures, encephalopathy, and strokelike events as part of the clinical presentation of MERRF; MELAS, and Leigh's disease. Oculopharyngeal muscular dystrophy (OPMD) is a repeat expansion disorder with onset in the fifth or sixth decade. Ptosis, ophthalmoplegia, and dysphagia and proximal weakness are common to both OPMD and KSS. Hearing loss, cerebellar ataxia, and cardiac conduction defects are not clinical features of OPMD but are seen with KSS. 35. A 28-year-old recently married woman with a clinical diagnosis of neurofibromatosis type 1 (NF1), characterized by an optic nerve glioma and multiple cutaneous neurofibromas and café-au-lait spots, comes to the office seeking reproductive advice. Which of the following is the most appropriate recommendation for this patient? A. Examination of her spouse for signs of NF1 B. Genetic testing for an abnormal NF1 gene to confirm the diagnosis C. Referral to a genetic counselor D. Tubal ligation or other form of permanent sterilization E. Therapeutic abortion if she becomes pregnant and prenatal testing is positive Correct Answer: The correct answer is C. This case underscores the importance of referring a patient with a genetic disorder to a geneticist or genetic counselor for a detailed discussion of reproductive risks and options. NF1 is autosomal dominant; this patient has a 50% risk of passing the NF1 gene to each of her children, although disease severity in an affected patient can be variable. Counseling about reproductive options and the role of possible 24 prenatal testing are best deferred to the genetics professional for this and other hereditable diseases. In addition, the neurologist should not let his or her personal beliefs interfere with the patient's freedom to reproduce or to access to prenatal testing and reproductive counseling. Examination of this patient's spouse is unnecessary because this is an autosomal dominant condition, and genetic testing in the patient is unnecessary presently as the patient already meets clinical criteria for the disease. 36. A 35-year-old man presents with a 6-month history of progressive dysarthria and mild dysphagia. Over the same period, he has noted tremor of the hands when he reaches for objects. He has had some nocturnal cramping in the legs but denies weakness in the limbs. He takes no medications and has been previously healthy. Family history is negative for neuromuscular disease. His mother died at age 60 of myocardial infarction, but his father is healthy at age 80. He has two sisters, one daughter, and two sons, all of whom are healthy. On examination, there is mild gynecomastia. He has evidence of tongue wasting, weakness, and fasciculation. Mild palate weakness is present. His speech is hoarse and breathy. Perioral fasciculations are present. He has mild upper and lower extremity weakness with rare fasciculation. The deep tendon reflexes are symmetrically reduced, and Babinski sign is absent bilaterally. Sensory examination is normal. His electromyography and nerve conduction studies show evidence of reduced compound motor action potentials with normal conduction velocities. The needle examination shows widespread fibrillations and large motor units, particularly in the tongue. Genetic testing reveals 55 CAG repeats in the gene coding for the androgen receptor gene. Which of the following is the most appropriate counseling for this patient? A. His life expectancy is about 3 years B. His sons each have a 25% chance of developing this illness C. His sister's children are at no risk of developing the disorder D. His daughters are all carriers of the affected gene E. The patient's creatine kinase (CK) level will be 10 times the normal value Correct Answer: The correct answer is D. This patient has spinobulbar muscular atrophy (SBMA or Kennedy's syndrome) as X-linked polyglutamine-coding CAG repeat expansion disease localized to Xq21-22. This gene codes for the androgen receptor gene encoding the male steroid receptor. Androgen receptor is expressed in motor neurons of the spinal cord and brain stem and mediates neurotrophic responses to androgen. Generally, this motor neuron disorder progresses much more slowly than ALS. Because it is an X-linked disorder, daughters of the male proband will all be carriers and sons will not inherit the gene. Assuming this patient inherited this gene from his mother, who was a carrier, his sister has a 50% of being a carrier of the gene. Therefore, her daughters each have a 50% chance of being carriers, and her sons each have a 50% chance of developing Kennedy syndrome. The patient's sister and his daughters should have genetic testing. His mother is dead and cannot be tested. Patients with Kennedy syndrome may have a slightly elevated CK, usually less than 5 times the normal value. 37. A 29-year-old woman presents with a 6-month history of progressive balance difficulties and falling. She reports tingling in her hands and loss of feeling in her feet. She states, "It feels like I'm walking on stumps." She denies weakness in the arms or legs but notes that she was always a slow runner and poor athlete. There have been no symptoms in the face and no change in bowel or bladder function. As a child and teenager she never noticed problems walking. As far as she knows there is no family history of peripheral neuropathy. She thinks her brother has "flat feet." Her examination reveals mild bilateral pes cavus and early development of hammertoes. There is no obvious atrophy in the lower legs or hands. She has symmetrical, mild, 4+/5 weakness in toe and ankle dorsiflexors. Strength is otherwise normal. The ankle reflexes are absent, and the other deep tendon reflexes are present but markedly reduced. The plantar responses are flexor. Sensory examination reveals reduced vibration sense to the level of the ankle with intact joint position sense. There is a stocking-glove loss to pin and temperature. Slight enlargement of ulnar and peroneal nerves is noted bilaterally. Nerve conductions studies reveal symmetrical reduction in sensory and motor action potential amplitudes and uniform slowing of conduction velocities in the 30 m/s range. Genetic testing reveals a duplication at chromosome 17p11.2 in the region containing the PMP22 gene. Which of the following features in this patient's presentation is the most helpful in differentiating her condition from chronic inflammatory demyelinating polyneuropathy? A. The family history of flat feet B. The presence of mild pes cavus C. The presence of nerve enlargement D. The uniform slowing of conduction velocities E. Marked reduction in the deep tendon reflexes Correct Answer: The correct answer is D. This patient has CMT1A, an autosomal dominant disorder due in most cases to a 1.4 Mb duplication at chromosome 17p11.2 in the PMP22 gene. The absence of a definite family history does not exclude the diagnosis of inherited neuropathy as there may be phenotypical variability in expression or the patient may have a new mutation. Pes cavus and planus are nonspecific findings and may be present with any 25 chronic disorder of the central or peripheral nervous system. Both acquired and inherited chronic demyelinating neuropathies may produce remyelination with nerve enlargement. In most patients with chronic inflammatory demyelinating polyneuropathy, the slowing seen on nerve conduction studies will be asymmetrical. CMT1A, in particular, and many inherited demyelinating neuropathies will have uniform conduction slowing. Deep tendon reflexes are typically reduced in both chronic inflammatory demyelinating polyneuropathy and CMT1A. 38. A 2-year-old boy presents with developmental delay, poor vision, and evidence of hypopituitarism. He was the product of a normal gestation and delivery. Since birth he has been in the fifth percentile for height, weight, and head circumference. Motor milestones are delayed, and he is just beginning to walk and use single words. He has had seizures since age 4 months that have been difficult to control on medications. On examination he is visually inattentive, the pupillary light response is absent bilaterally, and bilateral optic disc pallor is present. Tone is increased and diffuse hyperreflexia is present. Blood work reveals evidence of panhypopituitarism. MRI of the head reveals agenesis of the corpus callosum and septum pellucidum and hypoplasia of the optic nerves and chiasm. This child's disorder is associated with which of the following factors? A. Young maternal age B. Maternal diabetes C. Maternal alcohol use D. Mutations in HESX1 E. All of the above Correct Answer: The correct answer is E. This patient has septo-optic dysplasia (de Morsier syndrome), a disorder of prosencephalic cleavage and development of anterior telencephalic structures. Clinical features include mental retardation, visual disturbance, seizures, quadriparesis, and hypothalamic-pituitary dysfunction. There may be agenesis of the septum pellucidum, corpus callosum, and hypoplasia of the optic nerves and chiasm, and infundibulum. This disorder may have many causes, including genetic (mutations of HESX1), teratogenic drugs, and other maternal factors (young maternal age and diabetes). 39. A 3-month-old girl presents with intractable infantile spasms and hypotonia. She is the product of a normal gestation and birth and is the first child of a 25-year-old healthy woman. The infant was hypotonic at birth, and Apgar scores were 7 and 9 at 5 and 10 minutes. The child has had feeding difficulties since birth, and seizures developed at age 2 months. On examination she has a dysmorphic face with low-set ears, temporal hollowing, hypertelorism, a high forehead, and upturned nostrils. She is hypotonic. An MRI of the head reveals complete agyria and posterior enlargement of the lateral ventricles. Genetic testing reveals a large deletion in the LIS1 gene on chromosome 17p. The child's father is found to have a balanced translocation involving 17p. Which of the following is the most appropriate counseling for the parents of this child? A. The child will have a normal life expectancy but will be neurologically disabled B. The seizures will become less frequent as the child develops C. The likelihood of subsequent offspring of the parents being affected is very small D. Amniocentesis with fetal karyotyping of subsequent pregnancies is advised E. This disorder can be identified on fetal ultrasound at 12-weeks gestation Correct Answer: The correct answer is D. This child has Miller-Dieker syndrome, a disorder in which more than 90% of patients have a large deletion of the short arm of chromosome 17. The deletion usually encompasses the LIS1 gene as well as adjacent genes. The child has severe lissencephaly with agyria due to a severe disorder of neuronal migration. A broad heterotopic neuron zone is often beneath the cortical surface. Gyri and sulci do not form. This disorder cannot be recognized by fetal ultrasound until after the 28th week, as cerebral gyri are not formed prior to this gestational age. Therefore, amniocentesis with fetal karyotyping is the only reliable antenatal diagnostic test in the first trimester of pregnancy. In most patients the deletion is a de novo mutation. However, if one of the parents harbors a balanced translocation of chromosome 17, the recurrence risk is high and the parents should be counseled accordingly. Affected individuals have severe deficits and usually die in the first few years of life. 40. A 15-year-old boy presents with clusters of hyperkinetic motor seizures that typically occur at night. There is a family history of seizures in his father and his paternal grandmother. Neurological examination is normal. Routine EEG is normal. Which of the following is the most likely diagnosis? A. Autosomal dominant lateral temporal lobe epilepsy B. Autosomal dominant nocturnal frontal lobe epilepsy C. Generalized epilepsy with febrile seizures plus (GEFS+) D. Myoclonic epilepsy with ragged red fibers E. Juvenile myoclonic epilepsy Correct Answer: The correct answer is B. Hyperkinetic seizures occurring predominantly at night suggest a frontal lobe origin. Additionally, the strong family history argues for autosomal dominant inheritance. Autosomal 26 dominant nocturnal frontal lobe epilepsy (ADNFLE) is a rare but well-characterized condition that fits this description. Ictal EEG of patients with ADNFLE may demonstrate seizure activity in the frontal lobes, but interictal recordings are usually nondiagnostic. Autosomal dominant lateral temporal lobe epilepsy causes simple partial seizures characterzed by acoustic or, less commonly, visual hallucinations unlike the seizures described in this patient. MERRF is a mitochondrially inherited cause of progressive myoclonic epilepsy and myopathy, not consistent with this patient's presentation. JME typically causes seizures upon awakening rather than at night, unlike this patient; in addition, interictal EEGs of patients with JME commonly show generalized spike-and-wave- discharges. Spinal Cord Disorder June 2005 TYPE A QUESTIONS (ONE BEST ANSWER) 1. A 39-year-old woman developed low back pain after she slipped and fell on an ice patch outside a restaurant. The following day, her legs suddenly gave out while she was walking. On examination, she has moderate weakness of both lower extremities, worse in the flexors than the extensors. She has bilateral Babinski signs and a sensory level for pain and temperature at about the T10 level with normal position and vibration sensation. A spinal magnetic resonance image (MRI) is normal except for a Schmorl's node in the T6 vertebral body. Which of the following is the most likely cause of her weakness? A. Embolic intervertebral disk material B. Epidural abscess C. Epidural hematoma D. Spinal cord contusion E. Vertebral artery dissection Correct Answer: The correct answer is A. The onset of symptoms after mild back trauma and the presence of a Schmorl's node at a nearby spinal level make it likely that this patient suffered fibrocartilaginous embolism (in which intervertebral disk material gains access to the vascular system of the spinal cord and causes a spinal cord infarction). The MRI scan makes epidural abscess or hematoma unlikely. While vertebral artery dissection can cause spinal cord infarction, this patient had low back pain but no reported neck pain after her fall, and the Schmorl's node favors fibrocartilaginous embolism. Spinal cord contusion undetectable on MRI is not a recognized condition. 2. A 60-year-old man underwent repair of a 7-cm thoracoabdominal aortic aneurysm. Upon awakening from the operation, he noticed inability to move his legs. Examination revealed a flaccid paraplegia with a sensory level at T10. Examination 3 months later reveals severe lower extremity weakness, absent knee jerks, and bilateral ankle clonus and Babinski signs. Which of the following findings is to be expected upon his evaluation at this time? A. Abnormal tibial somatosensory evoked potentials B. Orthostatic hypotension C. Fibrillation potentials in the gastrocnemius muscles D. Bladder detrusor-sphincter dyssynergia E. Decreased amplitude sural nerve action potential Correct Answer: The correct answer is D. The patient suffered a spinal cord infarction in the territory of the artery of Adamkiewicz, which is a prominent anterior spinal artery feeder that originates between T9 and T12 and can be damaged during aortic repairs in this region. Anterior spinal artery territory infarctions affect the anterior two thirds of the spinal cord and preserve the dorsal columns. In this case, a sensory level at T10 and the pattern of segmental reflexes indicate a lesion extending to the L4 spinal segment but sparing the segments below. This will produce, upon recovery from spinal shock, a spastic bladder with detrusor hyperreflexia and detrusor-sphincter dyssynergia. Lesions below T9 spare the excitatory input to spinal sympathetic vasoconstrictor neurons and thus do not lead to orthostatic hypotension. Anterior spinal artery territory infarction typically spares the dorsal column, and, therefore, tibial sensory evoked potentials are expected to be unaffected. 3. Which of the following tests would be most appropriate in a 50-year-old woman with slowly progressive spastic paraparesis in whom testing reveals no evidence for structural neurological disease, inflammatory or motor neuron disease, vitamin B 12 deficiency, or motor neuron disease? A. Androgen receptor gene B. Dystrophin C. Emerin D. FMR1 gene E. Very long chain fatty acids Correct Answer: The correct answer is E. As many as 50% of female carriers of the gene for adrenoleukodystrophy (an X-linked, recessive disorder) develop myelopathy, although their condition is usually milder and tends to manifest at an older age than does typical adrenoleukodystrophy or adrenomyeloneuropathy in males. The [...]... Elevated interleukin-6 and 1 4-3 -3 proteins Correct Answer: The correct answer is E Increased levels of interleukin-6 or 1 4-3 -3 proteins in CSF may predict the severity of long- term disability in patients with transverse myelitis 26 A 46-year-old man with systemic lupus erythematosus and nonbacterial thrombotic endocarditis suddenly developed bilateral leg weakness Examination reveals flaccid paraplegia... increased T2 signal, and an area of gadolinium enhancement in the upper thoracic cord MRI of the head is normal Which of the following CSF findings may most likely correlate with long- term disability in this patient? A Markedly elevated IgG index and oligoclonal bands B Marked lymphocytic pleocytosis C Elevated angiotensin-converting enzyme D Increased complement C3 and C5 fractions E Elevated interleukin-6... moiety of methylcobalamin, interfering with methylation reaction, including transformation of homocysteine to methionine 8 A 35-year-old woman is evaluated for onset of back pain and progressive leg weakness and numbness over the past 2 days and difficulty voiding over the past 18 hours The first priority in evaluating this patient is determining whether: A The cause is vascular or inflammatory B A compressive... sense in the toes She has pes cavus The rest of her examination is unremarkable MRI of the head and spine and CSF examination are unremarkable The most likely cause of this patient's condition is a mutation of a gene encoding which of the following proteins? A Proteolipid protein B Myelin basic protein C Spastin D Paraplegin E Spartin Correct Answer: The correct answer is C The history and findings... Since a likely cause of spinal cord infarction is already known, there is no reason to look for evidence of inflammation or a vascular abnormality, and somatosensory evoked potentials would not add anything to the examination findings already available 27 A previously healthy 18-year-old man had sudden onset of back pain, leg weakness, and inability to void within 36 hours after lifting exercises in. .. than idiopathic or postinfectious transverse myelitis? A Asymmetrical weakness B Cerebrospinal fluid (CSF) pleocytosis C Elevated immunoglobulin (IgG) index D Enhancing spinal cord lesion on MRI E Progression to nadir within 2 hours Correct Answer: The correct answer is E Spinal cord inflammation (demonstrated by CSF pleocytosis, elevated IgG index, or a gadolinium-enhancing spinal cord lesion on MRI)... the HSP60 gene on chromosome 2q, have been linked to autosomal dominant, pure forms of disease (SPG13) 11 A 3 2- year-old man with AIDS complains of progressive leg weakness, paresthesias, gait unsteadiness, and urinary incontinence He is receiving antiretroviral therapy Examination reveals spastic paraparesis, sensory ataxia, and loss of joint position and vibration sense in the toes Tibial somatosensory... 1% 25 A 64-year-old man presents with a 2- day history of back pain and rapidly progressive weakness and numbness in the lower limbs associated with inability to void Neurological examination reveals flaccid weakness in the iliopsoas, hamstring, and foot muscles bilaterally, a pinprick level at T4, and loss of vibration and position sense in the toes MRI of the spine shows segmental enlargement, increased.. .27 diagnosis is established by measuring very long chain fatty acids in plasma, especially the C26:0/C 22: 0 ratio Female carriers of spinobulbar muscular atrophy, Duchenne's muscular dystrophy, Emery-Dreifuss muscular dystrophy, and fragile X syndrome do not develop myelopathy 4 A 25 -year-old man developed a rapidly progressive paraparesis with a sensory level at T8 Which of the following features... oligoclonal bands in the CSF and the presence of a circulating neuromyelitis optica antibody in serum 14 A 22 -year-old man with history of intravenous drug use presents with a 6-week history of progressive difficulties with gait and urinary urgency Examination reveals weakness and spasticity in the lower limbs Urodynamic study reveals overactive detrusor contractions with detrusor-sphincter dyssynergy . Elevated interleukin-6 and 1 4-3 -3 proteins Correct Answer: The correct answer is E. Increased levels of interleukin-6 or 1 4-3 -3 proteins in CSF may predict the severity of long- term disability in. encoding which of the following proteins? A. Proteolipid protein B. Myelin basic protein C. Spastin D. Paraplegin E. Spartin Correct Answer: The correct answer is C. The history and findings. A. The pattern of inheritance suggests an X-linked dominant condition (no male-to-male inheritance), although an autosomal dominant condition remains a possibility. The X-linked form of CMT,