Neurodegenerative Disorders Flashcards
Most common hereditary ataxia
Autosomal recessive (only AR trinucleotide repeat disorder)
Children present with gait ataxia, early fatigability
Progressive gait ataxia
Sensory and cerebellar due to dysfunction of the spinal cord, cerebellum, and peripheral nerves
Dysarthria, scoliosis, diminished or absent reflexes, cardiomyopathy, deafness, oculomotor abnormalities
Caused by GAA expansion in intron of Frataxin gene involved in mitochondrial iron metabolism
Friedreich’s Ataxia
Most are autosomal dominant
Caused by degeneration of the spinal cord and the cerebellum
Characterized by the following
Slowly progressive ataxia
Poor coordination of hands, speech, and eye movements
Usually mental capacity is maintained
About 30 types have been identified
Many are caused by CAG repeats, except SCA8 which is caused by a CTG repeat
Most have varying phenotypes but there is overlap
Often diagnosed using a panel testing strategy
Spinocerebellar ataxia
Progressive cerebellar ataxia
Oculocutaneous telangiectasia
Onset 3-6 years typically on the eyes and ears
Abnormal cellular and humoral immunity
Recurrent/viral and bacterial infection
ATM gene, autosomal recessive
11q22-23
Incidence 1/80,000-100,000
ataxia telangiectasia
Autosomal dominant, variable expressivity but 100% penetrance by 5 years
Incidence 1/3000
Caused by mutations in neurofibromin, a tumor suppressor gene
50% of cases are new mutations
clinical diagnosis requires two or more of the following:
6+ café-au-lait spots or macules greater than or equal to 5mm in diameter in prepubetal patients and 15mm min in postpubertal patients
2+ neurofibromata of any type, or one plexiform neurofibroma
freckling in the axillary or inguinal region
optic glioma
2+ Lish nodules (iris hamartomas)
distinctive osseous lesion (sphenoid dysplasia, cortical thinning of long bones, pseudoarthrosis)
first degree relative with NF-1 according to preceding criteria
phenotype evolves with time
increase in cafe-au-lait spots as child ages
other disease manifestations become apparent in late childhood or teenage years
complications: direct involvement of plexiform neurofibromas and risk of malignant transformation (fibrosarcomas), learning disability, seizures, hypertension, short stature, abnormal puberty, and pheochromocytoma
Neurofibromatosis 1
autosomal dominant disorder with complete penetrance, variable expressivity, and high new mutation rate
incidence 1/40,000
caused by mutation in Merlin, a cytoskeletal protein on chromosome 22
diagnostic criteria:
bilateral vestibular schwannomas or a first degree relative with NF2 and one of the following-
unilateral vestibular schwannoma under 30 years of age
two of the following- meningioma, glioma, schwannoma, juvenile posterior subscapular lenticular opacities/juvenile cortical cataract
Neurofibromatosis 2
multi-system disease
autosomal dominant, variable expressivity
high spontaneous mutation rate
incidence 1/6000
mutations in either TSC1 (9q34, hamartin) or TSC2 (16q13, tuberin)
similar to NF1 and NF2 in that clinical criteria make diagnosis and assessments vary with age
major criteria: facial angiofibromas or forehead plaque non-traumatic ungual or periungual fibroma hypomelanotic macules Shagreen patch (connective tissue nevus)
other features: epilepsy infantile spasms learning disability autism renal failure
Tuberous sclerosis
rare, genetic disorder characterized by the breakdown or loss of the myelin sheath surrounding nerve cells in the brain
accumulate high levels of saturated, very long chain fatty acids in the brain and adrenal cortex because fatty acids are not broken down normally
progressive dysfunction of the adrenal gland
X-linked recessive
Classic childhood form:
Most severe, only affects males, onset ages 4-10
Visual loss, LD, seizures, dysarthria, dysphagia, deafness, disturbances of gait and coordination, fatigue, intermittent vomiting, melanoderma, progressive dementia
Behavioral changes (often misdiagnosed as ADHD): Abnormal withdrawal or aggression, Poor memory, Poor school performance
All males with primary adrenocortical deficiency +/- neurological abnormality
Neuromuscular form:
Young or middle aged men
Progressive gait disorders, leg stiffness or weakness, abnormalities of sphincter control and sexual dysfunction, with or without adrenal insufficiency or cognitive or behavioral deficits
Milder adult-onset form:
Begins between ages 21 and 35
Leg stiffness, progressive spastic paraparesis (stiffness, weakness, paralysis) of the lower extremities and ataxia
Progresses more slowly than the classic childhood form but can also result in deterioration of brain function
Neonatal form:
Affects both male and female newborns
Mental retardation, facial abnoramlitis, seizures, retinal degeneration, hypotonia, hepatomegaly, adrenal dysfunction
Typically progresses quickly
Symptomatic female carriers:
Due to skewed X-inactivation
Milder symptoms
Spastic paraplegia of the lower limbs, ataxia, hypertonia, mild peripheral neuropathy, urinary problems
Adrenoleukodystrophy (ALD)
Group of autosomal recessive disorders in which breakdown products accumulate in nerve cells, histiocytes, and other cells
most common (1/12,500) heritable progressive encephalopathies of children
Infantile (INCL) / Late infantile (LINCL):
Myoclonic seizures, retinal degeneration leading to chronic encephalopathy and blindness, brain atrophy
Caused by lysosomal palmitoyl protein thioesterase (PTT) deficiency
PTT catalyzes the hydrolysis of thioester linkages in S-acylated polypeptides, deficiency causes abnormal accumulation of these polypeptides
Drugs with nucleophilic properties (Cystagon) may be effective because thioester bonds are susceptible to nucleophilic attack
Juvenile (Batten):
Progressive visual loss followed by retinal pigmentary changes, dementia, seizures
Adult (Kuf’s disease):
Psychiatric manifestations
Genotype does not predict age of onset, or reliably predict phenotype
There is a spectrum of phenotypes associated with certain genes
Some genes have phenotypic homogeneity
Shared features: Neurodegeneration Retinopathy Epilepsy Dementia Movement disorder Intracellular storage material
Neuronal ceroid lipofuscinosis (NCL)
Oculogyric crises, parkinsonian symptoms, tremor, hypokinesia, truncal hypotonia, irritability, and alterations in tone (hypotonia spasticity)
Diagnosis by CSF neurotransmitter studies
Decreased CNS catecholamine levels, serotonin metabolism is unaffected, tetrahydrobiopterin and neopterin levels are normal
Autosomal recessive
3 missense mutations in TH gene have been identified
Tyrosine hydroxylase deficiency
generalized epilepsy
Presents in the first year of life as prolonged and recurrent febrile seizures with generalized or hemiclonic activity
In the second year of life – developmental delay, myoclonic/partial/absence seizures noted
Diagnostic criteria:
Onset febrile seizures less than 7 months
5+ seizures
prolonged seizures lasting 10+ minutes
most cases are de novo
treatment: specific anti-epileptics
Drevat and related syndrome
Familial epilepsy syndrome encompassing a spectrum of conditions ranging from febrile seizures to severe epilepsies (Drevat), with several family members affected
Counseling more difficult because of the phenotypic variability within families
Associated genes: SCN1A, SCN1B, GABRG2, PCDH19 (only females)
Infantile spasms:
Age-limited type of seizure + hypsarrhythmia + developmental delay
20% idiopathic “West syndrome”
common chromosomal epilepsies: 1p36 deletion syndrome Wolf-Hirschhorn syndrome (4p-) Angelman syndrome Miller-Dieker syndrome 15q inversion-duplication Ring chromosome 14 Ring chromosome 20 Down syndrome
Genetic epilepsy with febrile seizures plus (GEFS+)
Polyglutamine triple repeat
CAG repeat in coding region of Huntingin 3-35 unaffected 36-121 disease state 40-50 adult onset >70 juvenile onset
AD late onset neurodegenerative disorder
Incidence 1/10,000
Cognitive impairment, chorea, depression, other psychiatric symptoms
Death 15-20 years after onset
Juvenile onset type rigidity, bradykinesia, epilepsy, accelerated disease course
Predictable atrophy of caudate and putamen
Loss of cortical pyramidal cells
Cerebellar atrophy in children
Huntington disease
Diagnostic criteria:
Below average cognitive functioning (IQ less than 70)
deficits in 2+ adaptive behaviors (communication, daily living skills, social skills)
onset before age 18
Genetic: Down syndrome, fragile X syndrome, Rett syndrome, Atypical Rett syndrome, Williams syndrome
Teratogenic: fetal alcohol syndrome
Congenital infection: Rubella
Birth injury: hypoxic ischemic encephalopathy
Intellectual Disability
X linked neurodegenerative disorder
Mainly females - Common cause of mental retardation in females
Mainly sporadic
MeCP2 protein binds to methylated DNA and acts as a transcription repressor, there is normally ubiquitous expression throughout the body
Due to mutations or deletions in MECP2 gene which controls gene expression
Severity is dependent on X inactivation
Prevalence 1/10,000-1/15,000
Onset of symptoms around 18 months
Regression of skills (normal until onset) Head growth deceleration Language skills lost Stereotypies replace purposeful hand use Autistic features Gait ataxia Seizures, abnormal breathing Kyphosis/scoliosis
affects the cortex and basal ganglia
Decreased brain weight
Reduction of neuronal size with increased packing density
Alterations in dopamine and glutamatergic neurotransmitter systems
Atypicalsyndrome = syndrome variant
Caused by mutation in CDKL5 gene on Xp22
Early onset encephalopathy, infantile spasms, severe global delay, profound intellectual impairment
Milder forms can present with MR + autistic features
Should be considered if the patient phenotype is similar to listed features or if syndrome is suspected but MECP2 testing is negative
Rett syndrome
X linked intellectual disabilities disorder
Anticipation with subsequent generations
16-25 per 100,000
accounts for 3-6% of intellectual disability in boys with a family history of intellectual disability and no birth defects
expressed in many cells, most abundant in neurons
99% due to expansion of a CGG repeat sequence in the 5’ untranslated region of the gene
CGG expansion > 200 in the first exon of the FMR1 gene hypermethylation of surrounding CpG island which decreases or abolishes gene expression
Males:
Coarse facial features, macrocephaly, hypotonia, prominent ears, post-pubertal macro-orchidism, connective tissue dysfunction, mental retardation, seizures, autism, ADD/ADHD
Phenotype may be subtle, suspect in any male with developmental delay
Females:
Extremely variable phenotype
50% carrying full mutation show mental impairment ranging from learning disability with normal IQ to severe MR
may see similar facial features as males
variability of phenotype likely due to X inactivation status of mutant chromosome
the mothers affected individuals are carriers of at least the premutation
when premutation is transmitted by males it usually does not increase in size
when the premutation is transmitted by females it usually increases in size
Fragile X Syndrome
