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Mito
100
Presents in teenage years with progressive ataxia, dysarthria/dysphagia, sensory loss due to axonal neuropathy, high-arched feet, and weakness with relatively intact cognition
Cardiomyopathy is the most common cause of death
disorder, gene, trinucleotide repeat
Friedreich Ataxia (FA)
loss-of-function mutation of the frataxin (FXN) gene caused by a trinucleotide repeat of GAA (>66)
100
infantile form will present with an exaggerated startle, fevers, behavioral regression, optic atrophy, and hypertonicity. Death usually occurs within a few years of diagnosis.
Pathology will show large globoid cells which are PAS-positive multinucleated macrophages
disease and what enzyme is deficient
Krabbe disease
deficiency of the enzyme galactocerebrosidase
100
Blood and urine studies can show increased levels of VLCFAs
Presents with adrenal failure, testicular atrophy, hyperactivity, ataxia, vision/hearing loss, and seizures
X-linked Adrenoleukodystrophy
GENE: ABCD1. mutation leads to impaired very-long-chain fatty acid (VLCFA) oxidation
100
Symptoms of weakness, cramping, and fatigue begin at 3-5 years of age with loss of ambulation by 13 years. Death secondary to respiratory or cardiac failure typically occurs in the second to third decade of life
pseudohypertrophy in calf muscles, a waddling gait, toe walking, and Gower’s sign
bonus is you know treatment
Duchenne muscular dystrophy (DMD)
GENE: dystrophin gene (DMD) resulting in complete loss of dystrophin. out-of-frame mutation
Dystrophin anchors the cellular cytoskeleton to actin, contributing to the stability of the plasma membrane
tx: Eteplirsen, which works by exon skipping of dystrophin mRNA, was recently FDA-approved for a subset of patients with DMD who have out-of-frame mutations on exon 51 of the dystrophin gene
100
appears in children/young adults (ages 2–15) with symptoms like recurrent stroke-like episodes (causing hemiparesis/blindness), seizures, severe headaches, muscle weakness, and dementia
MELAS syndrome (mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes)
200
Presents between ages 5 and 35 years with hepatic, neurologic, and psychiatric symptoms
Neurologic symptoms include dysarthria, ataxia, and dystonia
Psychiatric symptoms include depression, irritability, and personality changes
high urine copper, low serum copper, and low ceruloplasmin.
Kayser-Fleischer rings are seen on slit-lamp examination
Wilson’s Disease
- Also known as hepatolenticular degeneration.
GENE: ATP7B gene on chromosome 13
Imaging: MRI FLAIR will show hyperintensities of the caudate, putamen, and midbrain
sparing of the red nucleus, also known radiographically as the “face of giant panda”
Tx: Chelation therapy (penicillamine, trientine) is the first-line treatment
200
early-onset gait disturbance, stroke-like episodes, cognitive decline/dementia, premature alopecia (hair loss), and severe lower-back pain (spondylosis)
Cerebral Autosomal Recessive Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CARASIL)
GENE: HTRA1 gene mutations
CADASIL (autosomal dominant, NOTCH3 gene) causes migraines, strokes, and mood disorders
200
most prevalent lysosomal storage disorder
Presents with a painful small fiber peripheral neuropathy with autonomic manifestations (anhidrosis)
defect in alpha-galactosidase which leads to the accumulation of globotriaosylceramide
Fabry disease
GENE: GLA gene
defect in alpha-galactosidase which leads to the accumulation of globotriaosylceramide
200
present similarly to DMD but will do so later in life
Becker muscular dystrophy
GENE: dystrophin gene in-frame mutation
200
Key symptoms include uncontrollable muscle jerks (myoclonus), seizures, ataxia (incoordination), and muscle weakness
Diagnosis is confirmed by identifying "ragged red fibers" in muscle biopsies
Myoclonic epilepsy with ragged red fibers
300
Presents in children between 1-2 years old with progressive cerebellar ataxia, telangiectasias, and recurrent sinopulmonary infections
Have elevated serum α-fetoprotein
higher risk of cancer, particularly lymphomas
Ataxia Telangiectasia (ATM)
GENE: ATM gene
Mnemonic: ATM: Ataxia, Telangiectasia, Mucus/Malignancy
300
Iron builds up in parts of the brain, leading to progressive parkinsonism, dystonia, dementia, personality change, vision loss, and ultimately death
Pantothenate-kinase-associated Neurodegeneration (PKAN)
mutation of the pantothenate kinase 2 (PANK2) gene
Imaging: Brain MRI will show the “eye of the tiger sign”
300
only X-linked urea cycle disorder
Symptoms arise from toxic ammonia buildup and can occur shortly after birth (neonatal) or later in life.
Within days of birth, infants may exhibit rapid breathing, lethargy, irritability, poor feeding, seizures, coma, and poor temperature regulation
Identified through high blood ammonia, elevated urine orotic acid, low citrulline
Ornithine Transcarbamylase Deficiency
GENE: OTC gene
300
neuromuscular disorder with triad of (1) pigmentary retinopathy (2) progressive external ophthalmoplegia (3) cardiac conduction abnormalities
typically presents at <20 years of age
Kearns-Sayre Syndrome (KSS)
400
most common cause of progressive motor neuron disease in infancy but can also present in childhood or as an adult
characterized by degeneration of the anterior horn cells resulting in progressive weakness, hypotonia, and atrophy
Spinal Muscular Atrophy
GENE: Survival motor neuron (SMN1) gene
tx:
In 2017, nusinersen, an antisense oligonucleotide delivered by intrathecal injection was FDA-approved as the first treatment for SMA type 1
More recently the FDA has also approved onasemnogene abeparvovec, an IV-administered adeno-associated virus vector-based gene therapy
Phenotypes of SMA types: “Type I, never sit; type II, never walk; type III, never run.”
400
A demyelinating sensorimotor polyneuropathy is also present in almost all cases
infants present with vision loss, spastic ataxia, and seizures. Death usually occurs in 2-4 years after disease onset
Imaging will show extensive white matter demyelination with sparing of the cortical U-fibers
Metachromatic leukodystrophy
deficiency of arylsulfatase A enzyme
mutation in the ARSA gene.
400
Patients present with slowly progressive lower motor neuron symptoms (weakness and atrophy) in the 4th to 7th decades of life
significant tongue, perioral, and chin fasciculations/atrophy.
X-linked Spinal Bulbar Muscular Atrophy/Kennedy's disease
GENE: unstable CAG expansion of the androgen receptor gene
400
Presents with hypotonia, developmental delay, intellectual impairment, infertility, and chronic overeating (hyperphagia)
syndrome and chromosome that is functional
Prader Willi
Only the maternal chromosome 15 related genes are functional
Occurs due to the deletion, mutation, or inappropriate methylation of the paternal copy of the q11-q13 segment on chromosome 15
400
mitochondrial disorder causing sudden, painless, progressive central vision loss, primarily affecting young adult males
Leber's hereditary optic neuropathy (LHON)
500
Regression, seizures, abnormal startle
A "cherry-red" spot in the macula of the eye
Risk Factors: Most common in individuals of Ashkenazi Jewish, French-Canadian, or Louisiana Cajun descent
Tay-Sachs disease
mutations in the HEXA gene, which leads to a deficiency of the hexosaminidase A (Hex-A) enzyme
Accumulation of GM2 ganglioside
500
Associated with adult-onset cerebellar ataxia
Can be seen in patients with cystic fibrosis, Crohn’s disease, short bowel syndrome
Exam: truncal and limb ataxia, decreased deep tendon reflexes, decreased vibratory and position sense
Ataxia with Vitamin E deficiency
GENE: alpha-tocopherol-transfer protein (a-TTP)
500
Presents with nystagmus, ataxia, and tremor at various ages based on the severity of the mutation
Pathology will show a diffuse absence of myelin with preserved myelin islets around blood vessels called “tigroid demyelination”
Pelizaeus-Merzbacher disease
GENE: proteolipid protein (PLP1) gene which is involved with myelin protein integrity
500
presents with delayed development, intellectual disability, ataxia, epilepsy, and a happy disposition with frequent smiling, hyperactivity, laughter, and hand-flapping
syndrome and functional chromosome
Angelman Syndrome
only paternal chromosome 15 related genes are functional
The maternal copy of chromosome 15q11-q13 is impaired
500
Onset is usually in early childhood (1-5 years) or adolescence
A seizure is the first symptom in half of patients, while others first present with failure to thrive, hypotonia, and developmental delay
Seizures are usually occipital
Valproic acid is an absolute contraindication due to its effect on mitochondrial metabolism
POLG-related epilepsy