AD and XL-D

AD

100

neurocutaneous disorder 

seizures, intellectual disability

Non-neurologic findings include ash-leaf spots, facial angiofibromas, angiomyolipomas, and retinal hamartomas, cardiac rhabdomyomas

5-10% of patients can develop subependymal giant cell astrocytomas 

Tuberous Sclerosis

GENE:TSC1 (9q34) which encodes hamartin and TSC2 (16q13) which encodes tuberin.

200

Optic nerve gliomas 

Non-neurologic findings include café-au-lait spots, Lisch nodules, skeletal abnormalities, and axillary freckling

What is the disorder, gene, and what does it encode?

Neurofibromatosis type I (NF-1)

GENE: NF1 gene, which codes for neurofibromin. 

Neurofibromatosis Type II (NF2):  NF2 gene, which codes for merlin on chromosome 22. 

Presents with vestibular schwannomas and multiple meningiomas. 

• Can have bilateral acoustic neuromas. Patients usually present in their 20s with tinnitus.

NF2 is a story of 2's: 2 nerves affected (typically CN VII or CN VIII), often on 2 sides (bilateral), 2 tumors (schwannomas, meningiomas), Chromosome 22.

 

300

choreiform movements, psychiatric problems, and neurocognitive deficits.

develop depression as well

imaging: caudate atrophy

Gene, location, and trinucleotide repeats?

Bonus: MOA of the med to treat 

Huntington's Disease

GENE: HD gene. Location 4p16.3 

Trinucleotide repeats >40 CAG leads to full penetrance of the disease (Repeats expand with each generation in an “anticipation” pattern)

MED: Tetrabenazine VMAT2. Deutetrabenazine 

Remember the rule of 4s for HD: 4p gene, >40 trinucleotide repeats, around 40 years at the age of onset, TETRAbenazine

400

recurrent febrile seizures beyond 6 years of age 

also have non-febrile generalized seizures 

gene encodes sodium channel subunits

Genetic epilepsy with febrile seizures plus (GEFS+)

GENE: SCN1A or SCN1B 

500

characterized by the onset of focal motor seizures, typically within the first week of life (days 2–7), in otherwise healthy infants. Seizures usually resolve spontaneously within weeks or months, with normal neurodevelopmental outcomes in over 90% of cases, though some may develop later epilepsy.

strong association with potassium channel defects  

Self-limited familial neonatal epilepsy (SeLNE)

AKA Formerly called benign familial neonatal epilepsy (BFNE), benign familial neonatal seizures (BFNS), or benign familial neonatal convulsions (BFNC) 

GENE: KCNQ2 

AD

100

myotonia as well as weakness of the face, neck, and intrinsic hand muscles

2 types 

what are the genes and nucleotide repeats

 

Myotonic dystrophy (MD)

Type 1 MD: myotonic dystrophy protein kinase (DMPK) gene.  CTG repeat 

Type 2 MD: CNBP gene. CCTG repeat 

EMG will show myotonic discharges (spontaneous potentials with waxing and waning amplitude and frequency)

200

Onset in age 40’s with ptosis, progressing to dysphagia, then proximal muscle weakness

Mutation of what gene?

 oculopharyngeal muscular dystrophy (OPMD)

PABPN1

300

length-dependent polyneuropathy and autonomic dysfunction

multiorgan (kidney, liver, GI) dysfunction

 Congo red staining, which reveals characteristic apple-green birefringence under polarized light. 

Hereditary transthyretin amyloidosis (hATTR)

mutated proteins: transthyretin (TTR), apolipoprotein A-1, or gelsolin proteins 

treatment: 

• Diflunisal (non-steroidal anti-inflammatory drug)
• Tafamidis (selective stabilizer of TTR)
• Patisiran (siRNA which reduces the production of TTR proteins)

400

 neonatal hypotonia and weakness

Muscle biopsy will show lucent central cores on NADH stain with variably sized fibers with internalized nuclei  

these patients are at a higher risk to develop malignant hyperthermia

Central core disease

GENE: ryanodine calcium channel (RYR1) 

500

 Late-onset ataxia, myoclonic epilepsy, and dementia, most commonly in Japanese

Dentatorubral-pallidoluysian Atrophy

GENE: ATN1 gene 

Repeat:  Trinucleotide expansion (CAG) 

AD

100

Patients develop infratentorial hemangioblastomas and retinal angiomas 

Non-CNS manifestations include renal cell carcinoma, pheochromocytomas, and pancreatic and renal cysts

Von Hippel–Lindau disease

GENE: VHL (a tumor suppressor) gene mutation 

200

Triggered by the use of anesthesia (typically succinylcholine)

Causes muscle rigidity, hyperthermia, autonomic instability, rhabdomyolysis, and altered mental status  

Malignant hyperthermia

GENE: RYR1 gene (ryanodine receptor 1)

Treatment: Stop the offending agent and give dantrolene: blocks release of calcium from the sarcoplasmic reticulum

300

Presents with weakness or sensory loss during the first two decades of life along with distal atrophy, hyporeflexia, palpable nerves, and high-arched feet 

Patients will require ambulation aids such as ankle-foot orthoses but will not lose the ability to ambulate

Pathology: Onion bulbs/hypertrophic neuropathy are the result of repeated episodes of demyelination and remyelination and are composed of concentric rings of Schwann cells  

Charcot-Marie-Tooth disease (CMT): 

CMT type 1A (CMT1A)

GENE: duplication of gene peripheral myelin protein (PMP22). chromosome 17p 

EMG will show demyelinating sensory and motor peripheral neuropathy

400

Presents with episodic ataxia, gait instability, and nystagmus.

Type I: last minutes. Triggered by startle and exercise 

Type II: last hours to days. Triggered by fatigue, stress, and alcohol. 

2 different genes for 1 and II, bonus if you know the treatments for each

Episodic Ataxia

Type I: Mutation to the voltage-gated potassium channel (KCNA1)

tx: Carbamazepine 

Type II: Due to point mutations to the voltage-gated calcium channel (CACNA1a) 

tx: Acetazolamide 

fyi: Mutations to the CACNA1a gene can cause familial hemiplegic migraine and spinocerebellar ataxia type 6 

500

Presents with impairment of memory and at least one other area of cognition 

Early symptoms include forgetfulness for recent events or newly acquired information, disorientation, and difficulty with complex cognitive functions

What is this and what is the most common single-gene cause?

Early-onset Alzheimer’s disease

GENE: Presenilin 1  

Most common single-gene cause of AD. It is autosomal dominant with 100% penetrance and located on chromosome 14 

Presenilin 2:Located on chromosome 1.

Amyloid precursor protein (APP): Located on chromosome 21.

• People with Down syndrome (trisomy 21) have a higher risk of Alzheimer’s disease due to the overproduction of APP

AD

100

temporary, recurring episodes of muscle weakness, stiffness (myotonia), or paralysis, usually triggered by rest after exercise, cold, or high-potassium foods 

Attacks typically last 15 minutes to an hour, often affecting shoulders, hips, and limbs 

usually before age 10 

Hyperkalemic periodic paralysis 

GENE: SCN4A voltage-gated sodium channel mutation 

200

temporary, recurring episodes of severe muscle weakness or flaccid paralysis, often starting in adolescence, where individuals remain conscious during attacks 

Symptoms include weakness in shoulders, hips, arms, and legs—often upon awakening or resting after exercise—which can last from minutes to days.

first to third decades 

Hypokalemic periodic paralysis

GENE: CACNA1S encodes L-type voltage-gates calcium channels

300

Presents with muscle stiffness provoked by cold, exercise, or hypokalemia

Paramyotonia congenita

GENE:  SCN4A voltage-gated sodium channel 

400

Presents with normal muscle strength, myotonia, and muscle stiffness between 2-3 years of age 

Patients will have normal or increased bulk, and muscle stiffness will improve with exercise

Myotonia congenita

GENE: chloride channel (CLCN1) gene. 

500

Presents in childhood as progressive dystonia of the lower extremities without any other significant comorbidities 

 females 

Symptoms are usually mild in the morning and worse at the end of the day (“diurnal”)

Dopa responsive dystonia

Symptoms are usually mild in the morning and worse at the end of the day (“diurnal”) 

GENE: Mutation of the gene GTP cyclohydrolase I (GCH1) 

XL-D

100

rare genetic neurodevelopmental disorder, primarily affecting girls, that causes severe, progressive loss of motor skills, speech, and purposeful hand use 

 typically appear after 6–18 months of normal development 

 repetitive hand movements, breathing irregularities, and seizures

Rett syndrome 

GENE: MECP2 gene 

200

most common single-gene cause of intellectual disability 

Presents with intellectual disability and stereotypies (hand wringing, clapping, or flapping)

Characteristic physical features include a long face, large ears, and hyperextensible joints 

Gene and number of trinucleotide repeats required

Fragile X Syndrome

GENE:  FMR1 gene 

• Requires >200 CGG trinucleotide repeats

300

Periventricular Nodular Heterotopia 

GENE: FLNA gene. Filamin A protein. 

400

Triad of agenesis of the corpus callosum, chorioretinal lacunae, and infantile spasms. 

no gene known yet but what is the condition...not to get confused with Aicardi-Goutières syndrome (AGS) 

Aicardi Syndrome