Neurological Disorders

A 7-month-old boy presents with severe developmental delay and intractable seizures. Brain MRI shows a smooth cerebral surface with markedly reduced gyri (lissencephaly). His older sister carries the same _DCX_ variant; she has a milder phenotype of childhood-onset epilepsy and mild intellectual disability, and her MRI shows bilateral symmetric bands of gray matter sitting beneath the cortical ribbon ("double cortex").

A prenatal ultrasound reveals a single-lobed brain with fused thalami and absent midline structures. The fetus has hypotelorism and a midline cleft lip.

A male infant is born with severe hydrocephalus requiring shunting. He has adducted thumbs and later develops spastic paraplegia. Family history is notable for 2 affected maternal uncles with similar symptoms.

A second trimester ultrasound shows enlarged echogenic kidneys, occipital encephalocele, and postaxial polydactyly. Oligohydramnios is noted.

A newborn with a small head has severe hypotonia and seizures. MRI reveals a smooth brain surface (agyria). CMA shows a 17p13.3 deletion.

A young woman with normal intelligence presents with adult-onset focal seizures. Brain MRI shows multiple smooth nodules of gray matter lining both lateral ventricles. Family history reveals a sister with epilepsy and a brother who died in utero with cardiac and skeletal malformations.

A fetus has severe ventriculomegaly on ultrasound. After birth, the infant has hypotonia, structural eye abnormalities (microphthalmia), and cobblestone lissencephaly on MRI.

A teenage boy has severe intellectual disability, coarse facial features with a prominent forehead and widely spaced eyes, and large soft hands with tapered fingers.

A 4-year-old boy with autism and developmental delays has a long face and prominent ears. His maternal grandfather has tremor and balance problems.

A 4-year-old boy has severe intellectual disability, infantile hypotonia that has evolved into progressive spasticity, no expressive language, and a history of multiple hospitalizations for recurrent pneumonia. His mother and maternal aunt are healthy. Chromosomal microarray shows a duplication at Xq28 spanning *MECP2*.

A 3-month-old male infant presents with seizures, hypotonia, and failure to thrive. He has sparse, kinky, colorless hair ("steel wool"). Labs show low serum copper and ceruloplasmin.

An 18-month-old girl who had been developing normally begins to lose purposeful hand skills and develops stereotypic hand-wringing movements. She loses language and develops breathing abnormalities.

A 10-year-old obese boy with rod-cone dystrophy is noted to have postaxial polydactyly (surgically removed at birth), learning difficulties, and small genitalia. Ultrasound shows renal structural anomalies.

A newborn has hypotonia and abnormal eye movements. Brain MRI reveals the characteristic "molar tooth sign" at the midbrain-hindbrain junction.

A newborn with a coloboma and choanal atresia fails the newborn hearing screen. He also has a congenital heart defect and genital hypoplasia.

A newborn has severe growth restriction, limb anomalies (absent forearm on one side), and distinctive facies with synophrys, a long philtrum, and thin lips.

A newborn has central polydactyly (insertional), imperforate anus, and a bifid epiglottis. MRI reveals a hypothalamic hamartoma.

A child with intellectual disability has distinctive facial features including arched eyebrows with lateral flaring, long palpebral fissures, and eversion of the lower eyelids. He also has fingertip pads.

A child with Hirschsprung disease, severe intellectual disability, and absent speech has distinctive facies with widely spaced eyes, broad nasal bridge, and uplifted earlobes.

A toddler with autism, absent speech, and global developmental delay has hypotonia and a high pain tolerance. CMA reveals a 22q13.3 deletion.

A child with severe intellectual disability and absent speech has episodes of hyperventilation followed by apnea. He has a distinctive happy demeanor and wide mouth with widely spaced teeth.

A child with intellectual disability has broad thumbs and great toes, a beaked nose, and highly arched eyebrows. He has a grimacing smile.

A teenager with a 5-year history of progressive cerebellar ataxia is unable to initiate horizontal saccades; head thrusts compensate ("oculomotor apraxia"). MRI shows cerebellar atrophy. Labs reveal hypoalbuminemia and elevated cholesterol with low albumin. Alpha-fetoprotein is normal (AOA1) or markedly elevated (AOA2).

A 12-year-old presents with progressive gait ataxia, dysarthria, and loss of reflexes in the lower limbs. He also has scoliosis. Echocardiogram shows hypertrophic cardiomyopathy.

A 40-year-old man presents with a 3-year history of progressive unsteadiness, slurred speech, and difficulty with fine motor tasks. His father had similar symptoms starting at age 50 and is now wheelchair-bound. Neurologic exam reveals gait and limb ataxia, dysarthria, and nystagmus. Brain MRI shows cerebellar atrophy.

A 35-year-old man with progressive gait ataxia and dysarthria has a father and two paternal aunts who developed similar symptoms at age 45. Genetic testing reveals a CAG repeat expansion in the _ATXN2_ gene.

A 6-year-old girl develops progressive gait difficulty with foot dystonia that worsens throughout the day and improves with sleep. Her symptoms dramatically resolve with low-dose levodopa. Her mother recalls similar childhood symptoms that were misdiagnosed as cerebral palsy.

A 52-year-old woman develops progressive memory loss and cognitive decline. Her mother and two maternal aunts died of early-onset dementia in their 50s.

A 55-year-old presents with personality changes, disinhibition, and language difficulties. Family history reveals a parent with similar dementia and an aunt who died of ALS.

A 40-year-old man develops involuntary choreiform movements, personality changes, and progressive cognitive decline. His father died in a psychiatric facility at age 50 with similar symptoms.

A 45-year-old man develops tremor, bradykinesia, and rigidity. Multiple family members across three generations have been affected with similar symptoms.

A 55-year-old man develops progressive muscle weakness, fasciculations, and atrophy. He has both upper motor neuron signs (spasticity, hyperreflexia) and lower motor neuron signs.

A 45-year-old man presents with several years of progressive proximal leg weakness, muscle cramps, and tongue fasciculations with mild dysarthria. He notes longstanding gynecomastia and reduced fertility. Reflexes are diminished without spasticity. Repeat-sizing of the _AR_ gene shows a CAG expansion of 47 repeats.

A 3-month-old infant presents with severe hypotonia, weakness, and tongue fasciculations. She has a frog-leg posture and paradoxical breathing. She never achieved head control.

A child who was normal at birth develops progressive growth failure, photosensitivity, and neurological regression. He has a characteristic cachectic appearance with sunken eyes.

A child of Ashkenazi Jewish descent has poor feeding, absent tears, and episodic vomiting with hypertension. He has a smooth tongue. His sister has similar symptoms.

A 45-year-old woman has recurrent strokes and a history of migraines with aura. Brain MRI shows extensive white matter lesions. Her father and grandmother both had early-onset strokes.

A patient with recurrent seizures and headaches has an MRI revealing multiple "popcorn-like" lesions with hemosiderin rings scattered throughout the brain.

A newborn has a port-wine stain (nevus flammeus) covering the forehead and upper eyelid. CT shows tramtrack calcifications in the brain. She later develops seizures and glaucoma.

A 12-year-old boy with mild proximal weakness and calf hypertrophy has an elevated CK. His maternal uncle is wheelchair-bound at age 40. Genetic testing shows an in-frame deletion in _DMD_.

A 4-year-old boy has difficulty climbing stairs and uses his hands to "walk up" his legs when rising from the floor (Gowers sign). His CK is markedly elevated at 15,000 U/L.

A teenager has elbow and ankle contractures and rigid spine. He has scapuloperoneal muscle weakness. His ECG shows heart block.

A 20-year-old has difficulty whistling and raising his arms above his head. He has scapular winging and facial weakness.

A young adult presents with progressive proximal weakness affecting hips and shoulders. CK is elevated. Genetic testing reveals a variant in a sarcoglycan gene.

A 50-year-old French-Canadian man presents with progressive bilateral ptosis and difficulty swallowing. He tilts his head back to see and has lost weight due to dysphagia. His father had similar symptoms starting in his 40s.

A neonate has hypotonia, weak cry, and feeding difficulty. Brain MRI shows lissencephaly type II ("cobblestone cortex") and cerebellar hypoplasia. Eye exam reveals retinal dysplasia and microphthalmia. CK is markedly elevated (2,000+). Biopsy shows dystrophic muscle and reduced α-dystroglycan glycosylation.

A 30-year-old man has difficulty releasing his grip after a handshake. He has frontal balding, bilateral ptosis, and cataracts. His mother and grandmother are also affected.

A 45-year-old woman has proximal muscle weakness and stiffness, cataracts, and myotonia. Her DM1 test was negative, but she has a CCTG expansion.

A teenager with high arches (pes cavus) and hammer toes has slowly progressive distal weakness and sensory loss. NCVs show uniformly slow motor conduction velocities.

A 25-year-old has recurrent episodes of numbness and weakness after minor nerve compression (e.g., crossing legs, leaning on elbow). Symptoms resolve over weeks.

During anesthesia for routine surgery, a 25-year-old develops rapidly rising temperature, muscle rigidity, hypercarbia, and metabolic acidosis. The anesthesiologist stops the triggering agents and administers dantrolene.

A neonate is born floppy with weak cry, poor feeding, and respiratory distress requiring ventilatory support. Facial weakness is prominent (myopathic face, tented upper lip). Muscle biopsy shows characteristic rod-shaped inclusions ("nemaline bodies") on Gomori trichrome stain. CK is normal or only mildly elevated.

A 6-year-old has multiple café-au-lait macules, axillary freckling, and Lisch nodules on slit-lamp exam. His father has similar skin findings and multiple dermal neurofibromas.

A 20-year-old presents with hearing loss and tinnitus. MRI reveals bilateral vestibular schwannomas. She also has multiple meningiomas and a spinal ependymoma.

An infant with infantile spasms is found to have hypopigmented macules (ash-leaf spots) and cardiac rhabdomyomas. Brain MRI shows cortical tubers and subependymal nodules.

A 6-month-old infant presents with recurrent episodes of hemiplegia that alternate sides. Episodes are triggered by stress, bathing, or temperature changes and resolve with sleep. Over time, the child develops developmental delay, dystonia, and epilepsy.

A teenager with focal epilepsy has an MRI showing focal cortical dysplasia. His father and brother have epilepsy but normal MRIs.

A newborn has frequent seizures starting on day 2 of life. Seizures are brief tonic events. By 3 months, seizures have resolved. Development is normal at follow-up.

A 6-month-old previously healthy infant has a prolonged febrile seizure lasting 30 minutes. He goes on to develop multiple seizure types refractory to medications and experiences developmental regression.

A toddler has intellectual disability, coarse facial features with a wide nose and full lips, sparse scalp hair with hypertrichosis of the face and back, and **hypoplastic or absent nails of the 5th fingers and toes**. Brain MRI shows agenesis of the corpus callosum.