Chap 39 - Degenerative D/o Flashcards by Josh Abejero

Two outstanding characteristics of degenerative disease.

affect specific parts or functional system of the nervous system
begin insidiously and then gradually progressive course

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Clinical Classification for Degenerative Dz

Syndrome of progressive dementia w/o other neurologic symptoms
Syndrome of posture and movement
Syndrome of progressive ataxia
Syndrome of slow muscular weakness and atrophy
Sensory and sensorimotor disorders
Syndrome of progressive blindness
Syndrome of degenerative sensorineural hearing loss

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Age onset in majority of AD

60’s or Older, but may rarely occur in late fifties or younger

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Familial occurrence AD characteristics:

1 % in dominant inheritance pattern w/ high chance of younger onset
Patients w/ less than 70 y/o likely to have relatives w/ similar illness

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Major symptom of AD

Gradual development of forgetfulness

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T/F. Remote memories are always preserved and recent memories are loss (Ribot’s law)

F. NOT ALWAYS TRUE . In ADs all aspects of memories are affected

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T/F. Social graces are first to affect in AD.

F. Memory dysfunction is the most common early manifestion, social graces usually occur in the latter part of illness

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Duration of AD in terms of :

Illness
Spinal fluid biomarkers & imaging prior to clinical manifestation

Illness: 5 year or more

Biomarkers & Imaging: if present 15 year or latter before they clinically manifest

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How many percent convulsion occurs in AD?

5% of infrequent seizures

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MCI syndrome is defined:

w/ cognitive impairment in one or more domain but no interference w/ ADLs

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5 opening/ early manifestation of AD

AMNESIA: most common and prominent; short and long-term memories affected while immediate memory not.
DYSNOMIA: name animal farms etc.
VISUOSPATIAL DISORIENTATION: ascociated w/ posterior cortical atrophy
PARANOIA & PERSONALITY CHANGE
EXECUTIVE DYSFUNCTION: coordinating/ planning task or following complex instructions

*** if any deficits remain stable over a long period of time think of other diagnosis

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Most disabling aspect of AD but not specific to it

Executive dysfunction

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NINCDS & ARDA criteria of AD (85% correct diagnosis of AD)

dementia by clinical exam, MMSE, or similar mental status exam
>40 y/o
2 or more deficits in cognition & worsening of memory
absence of disturbed consciousness
exclusion of other disease

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Gross changes of brain in AD

Diffuse atrophy, w/ weight reduction by 20%
Sulci widened
Extreme atrophy of hippocampus (diagnostic in proper clinical circumstances)

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Earliest most pronounced microscopic changes in AD

Cell loss in layer II of entorhinal cortex

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Predominantly affected cell loss in the cerebral cortex among AD

Large pyramidal neurons

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3 distinctive microscopic changes in AD

NEUROFIBRILLARY TANGLES composed of tau proteins in helical filaments
AMYLOID surrounded by neurotic plaques ( spherical deposits in PAS stain) & congophilic angiopathy
GRANULOVACUOLAR DEGENERATION: evident in pyramidal layer of hippocampus

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Microscopic pathologic changes correlate best w/ severity of dementia

Neurofibrillary tangles & neuronal loss. NOT amyloid plaques

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Areas of brain disproportionately affected in AD

Hippocampus (CA1 & CA2 zones)
Entorhinal cortex
Subiculum
Amygdala
Parietal lobe

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TAU-pathies in neurodegenerative disorders

Alzheimer’s Disease (AD)
Frontotemporal Dementia (FTD)
Progressive supranuclear palsy (PSP)

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Cytoskeletal protein promotes assembly of microtubules, stabilize structure or promotes synaptic plasticity

Tau protein: compose of beta-2 transferrin

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Ratio critical to neuronal toxicity of amyloid in AD

AB42: AB40 ratio; AB42 is toxic in several models of AD

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AD is related to APP gene found in what chromosome?

Chrom 21 (hence Down syndrome may have AD)

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Major portion of cholinergic terminals originate which is affected in AD

Nucleus basalis of Meynert / forebrain nuclei

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The genetic marker for AD susceptibility (3x risk of sporadic AD)

Apo-E4; also correlates w/ increased deposition of beta-amyloid

The presence of Apo-E4 accelerates appearance of AD by how many years?

5 years

Areas in the brain showing decrease blood flow in SPECT and metabolism in PET

Parietal association cortex, medial temporal lobe

Possible biologic marker of AD in CSF

Low AB42:tau ratio

Genetic & modulating factors associated w/ AD

Table 39-1 ADAMS

How large is the effect of dementia drugs is?

Modest. Ability to sustain an independent life but medication should be taken 6-12 months

NMDA antagonist used for dementia and therapeutic doses, indication and SE

Memantine D: 20mg/d I: for late stage AD as adjunct w/ cholinergic drugs SE: hallucinations & agitation

Monoclonal antibody at soluble forms of amyloid for tx of AD but failed w/ early AD

Solanezumab

T/F. Amyloid plaques & tangled deposition are far more common in PD (20-30%) compared to age-matched controls

TRUE (p. 1073)

Pathologic changes in Lobar Atrophies

* Atrophy is asymmetrical * Gyri paper thin / narrowing of cortical ribbon * grayish and reduced vol of underlying white matter (unifying element in this group)

FTD / Pick's disease has unique deposition of:

Pick bodies (argyrophilic intracytoplasmic inclusion) Pick cells (diffuse staining ballooned neurons)

2 Variants of FTLD

* Behavioral variant * Language variant * Semantic Dementia * Progressive non-fluent aphasia * Logophenic

Clinical manifestation of Behavioral Variant FTLD:

* Personality changes * Impaired insight * Depression (most common initial diagnosis) * Compulsive behavior * Hyperphagia / hyperorality (late stage)

Clinical manifestation of Progressive Nonfluent Aphasia FTLD

* Word finding but language structure is intact * Dysarthria & apraxia then becoming mute (late)

Clinical manifestation of Semantic Dementia in FTLD

Dysnomia Verbal perseveration but fluency retained Aware they are having trouble w/ words Prosopagnosia Memory of day-to-day is preserved

Progressive loss of ability to understand and use visual information May have fragments of Balint (simultagnosia, oculomotor apraxia & optic ataxia) & Gertsmann syndrome

Posterior Cortical Atrophy

Most frequent pathologic diagnosis next to AD

Lewy-body dementia (LBD)

Main components of Lewy-body Dementia

Ubiquitin & alpha-Synuclein

Features of LBD

* Parkinsonian (usually symmetric) * Flactuating nocturnal delirium or dementia * REM sleep behavior d/o \*\*\* 2 out of 3 is diagnostic of LBD

T/F. Parkinsonian feats of LBD respond favorably w/ L-dopa

TRUE. But for a limited time it may cause delirium or hallucinations

Drug use in LBD reducing delusion, hallucinations, anxiety

Rivastigmine (anticholinesterase inhibitor)

Connected w/ late life dementia preceded by behavior disturbances deposited w/ inclusion not related to LBD & AD

Argyrophilic Grain Disease

Adult onset dementia w/ fulminant evolution suggestive of encephalopathy & seizure

Neurserpinopathy, associated w/ neuroseprin (PAS + intraneuronal inclusion, large eosinophilic)

Triad of Huntington’s disease

* Dominant inheritance * Choreoathetosis * Dementia

Onset of Huntington’s Dz

* 4^th to 5^th decade of life but 3-5% may occur before 15 y/o * Progression is slower in older patients

Genetic abnormality in Huntington’s disease

Excessive long CAG repeats (more than 34) in chromosome 4

T/F. Length of repeat of CAG in Huntington’s is directly proportional w/ age of onset and severity

FALSE. Inversely proportional to age of onset BUT TRUE for severity

2 gross pathologic abnormality in Huntington’s Disease

* Head of caudate & putaminal atrophy * Gyral atrophy in frontal & temporal region * Lateral ventricles enlarge (secondary)

T/F. Larger neurons are affected before smaller neurons in Huntington’s disease

FALSE. Small spiny neurons affected first

Number of CAG repeats that confirms diagnosis & give expected time of onset in Huntingtons

39 CAG repeats

Drug effective partially in suppressing movement d/o & somehow alleviate behavioral & emotional abnormalities in Huntingtons

Haloperidol (2-10mg/day): dopamine antagonist; treat only if movement is disabling

Drugs that suppress chorea to some degree but SE outweigh for Huntingtons

Reserpine Clozapine Tetrabenzine

Average duration of illness from onset to death in Huntingtons

15-20 years

Disease w/ the ff characteristics: 1. adolescent of generalized involuntary movement 2. mild to mod mental deterioration 3. chronic axonal neuropathy (DTRS dec or absent) 4. thorny/ spiky erythrocytes

Neuroacanthocytosis

X-linked acanthocytosis, chorea & myopathy (KX protein)

McLeod disease

An inherent defect in RBC lipid membrane, associated w/ chromosome 9q and protein chorein. Manifest as dystonia, tics, vocalizations, cognitive impairment & psychiatric feats at middle age

Bassen –Kornzweig disease

Progressive parkinsonism & dementia w/ combined LMN & UMN signs among men 50-60 y/o from Pacific Islands

Guamanian Parkinson-Dementia-ALS complex

Progressive spasticity, chorea, dementia and sensory polyneuropathy. Presence of basophilic PAS+ in axons & astrocytes

Adult Polyglucosan Body Disease

Epidemiology of PD: Peak onset of PD & interval Sex Demographics

* 6^th decade of life, 45-70 y/o * Predominantly male * Across countries, races, socioeconomic class

Core features of PD

Postural instability Bradykinesia Rigidity Resting tremors

4 most common initial symptom of PD from first to 4th

* Tremor (70%) – most common * Gait disturbance * Stiffness * Slowness

Least degree of tremor felt during passive movement of rigid part

Negro sign

Parkinson resting tremor described as:

3-5 Hz tremor

Activation procedure eliciting rigidity by engaging the opposite limb w/ a motor task

Froment sign

T/F. The bradykinesia is derived from the rigidity of the illness

FALSE. It is independent from each other

Resistant to treatment in PD that sometimes are early finding

Extension or clawing of toes, jaw, clenching, & fragments of dystonia

A complication of PD where there is extreme forward flexion of spine, & severe stooping (axial dystonia), NOT RESPONSIVE TO L-DOPA

Camptocormia

Most advance PD, capable of remarkably brief effective movement

Kinesis Paradoxica

Inability to inhibit blinking upon tapping glabella or bridge of nose in PD

Myerson sign

Nonmotor Parkinsonian symptoms

* Pain / discomfort in calves abdomen * Drooling * Autonomic * Dementia * Depression

Estimate incidence of dementia in PD

10-15% increasing w/ age & duration of illness

Mean period of onset of PD to chairbound state

7.5 years

Mean duration where idiopathic PD acquires dyskinesia in L-dopa

3-5 years

Lower-half parkinsonism is associated with what?

Vascular parkinsonism, not responsive to L-dopa

Tremors of essential tremors differs from PD:

Essential tremors: 4-8 Hz fine tremors occurring volitional, attenuated by alcohol & propranolol PD tremors: 3-5 Hz,

Most constant & pertinent finding in idiopathic PD & postencephalitic PD

Loss of pigmented cells in substantia nigra & other pigmented nuclei ( locus ceruleus, DMN of vagus)

IDENTIFY THE INCLUSION BODY

Lewy Body, eosinophilic cytoplasmic inclusion w/ faint halo

T/F. All inherited and postecephalitic PD have Lewy Body

FALSE

Rate limiting enzyme for synthesis of dopamine

Tyrosine-hyroxylase

The absolute reduction of pigmented cells in PD compared to controls

66%

According to Braak’s, the earliest changes in brain among PD occurs in

Dorsal glossopharyngeal-vagal & anterior olfactory nuclei, later only in SN

The neurotoxin to cause irreversible signs of parkinsonism and selective destruction of SN: Its analogue drug is:

* MPTP * Meperidine

Familial occurrence in PD suggest by how many?

15%

Main components of Lewy body seen in inherited & sporadic PD

Alpha-synuclein & ubiquitin

Lewy body are not found in what gene mutation in PD

Parkin gene: (PARK2)

Accounts to 50% of early onset inherited PD, 20% of sporadic early-onset

PARK2 (Parkin)

Ubiquitin protein ligase that participates in removal of unnecessary proteins from cells in the proteosomal system

Parkin

PD gene mutation related to Gaucher disease

LRRRK2 (leucine-rich repeat kinase 2)

PD gene: normal function is to specify identity of dopaminergic neurons; confers to susceptibility to PD

NURR1 (NR4A)

PD gene: normal function essential for normal neuronal response to oxidative stress

DJ-1 (Park 7)

PD gene: mitochondrial gene & AR

PINK1 (Park 6)

The most effective agent for treatment of PD

L-dopa

Nigral neurons become inadequate & striatal neuron become excessively sensitive; Explanation of dyskinesia in L-dopa

Denervation hypersensitivity

Increases bioavailability, prevents peripheral decarboxylation in peripheral tissue & reduces peripheral SE

C-dopa or Bensarizide

Extends plasma half-life & duration of L-dopa by preventing breakdown

COMT inhibitors (entacapone)

Offer longer effect & reduce dyskinesia in advance stages. Facilitate morning rigidity & tremor when given at late evening

Long-acting CL Dopa (BUT 70% has inconsistent absorption)

Direct dopaminergic effect to striatal neurons , less potent than L-dopa but fewer dykinetic complications

Dopamine agonist

Ergot derivative dopamine agonist acting on D2 receptors

Bromocriptine and Lisuride

Non-ergot derivative dopamine agonist for PD

Ropinorole & Pramipexole

Dopamine agonist no longer used due to risk of cardiac valvular damage at high dose

Pergolide & Cabergoline

Allows gradual reduction of L-dopa dose by 50% & reducing motor fluctuations

Dopamine agonist

Transdermal dopamine agonist, with doubling of “on’ time & w/o dyskinesia

Rotigotine

Drug used for predominantly tremors among PD.

Anti-cholinergics (Trihexylphenidyl & Benztropine)

Notorius SE of use anticholinergics among elderly

Mental slowing, confusion, hallucinations

Antiviral agent w/ mild to moderate benefit for tremor, hypokinesia, postural symptoms. Reduce L-dopa induced dyskinesia

Amantidine (100mg BID)

Neuroprotective agent by reducing oxidative stress in dopaminergic neurons

MAO-B inhibitor (Rasagiline)

Antioxidant offer marginal advantage on progression by 6-18 months

CoQ10

On-off phenomenon occurs in PD by

75 % in 5 yrs

When involuntary movement occurs w/ small dose of L-dopa it can be addressed by

* Adding dopamine agonist or amantadine * Use of oral suspension (w/ ascorbic acid)

Onset of psychiatric symptoms occur in PD by

15-25% especially in advanced stage & elderly

Treatment options for psychosis in PD using

Atypical neuroleptics: Olanzapine, Clozapine, Risperidone, QuetiapineTreatment options for psychosis in PD using

Atypical anti-psychotic drug w/ additional benefit to suppress dyskinesia in advance PD, w/ limitation due to hematologic risk

Clozapine

Targets of DBS in PD

STN & GPi

Benefits of DBS in PD:

* Enhanced responsiveness of L-dopa & reduction of dyskinesia * Improve in all features of PD

Ideal candidate of DBS for PD

Failure to relieve symptoms w/ meds & difficult to treat dyskinesia

When dystonia present in PD, target in DBS show more benefit

GPi

Hypotensive episodes in PD can be managed w/

Fludrocortisone or Midodrine

T/F. There were neuronal loss in zona compacta in SN but no Lewy body or neurofibrillary tangles present & secondary pallidal atrophy

TRUE (p1095)

Orthostatic hypotension occurs and proven to be cell loss of:

Intermediolateral horn cells & pigment nuclei of brainstem

Features that may distinguish it MSA from PD

* Relative symmetryof sign & rapid * Lack of response to L-dopa (striatal loss of dopamine receptors) * Minimal amount of tremor * Early signs of autonomic dysfunction \*\*\* Anterocollis

Seen in MRI among MSA-C reflecting atrophy of pontocerebellar fibers in T2 sequence

Hot Cross Bun Sign

Mutation of gene related to MSA

COQ2 gene

Cytoplasmic aggregates seen in MSA not clear if histopathologic hallmark of it

Glial cytoplasmic inclusion

Typical onset of age in PSP

6th decade

Most common early complaint of PSP

Unsteadiness of gait & falling w/o LOC

T/F. A proportion of PSP patients demonstrate eye signs w/in a year

FALSE

Distinguishing PSP from PD:

* Tonic grimace * Lack of tremor * Erect posture * Prominent oculomotor abnormalities

PE in PSP, where patient fails to stop clapping even if asked to clap 3 times only

Applause sign

MRI findings found in PSP:

Mouse ears: atrophy of dorsal mesencephalon Hummingbird sign

Neurofibrillary tangles associated w/ PSP

Tau

Genetic implication for PSP

Chromosome 17p

Drugs can be used for PSP

L-dopa: slight unsustain benefit Zolpidem: ameloriate akinesia & rigidity Anticholinergics: dystonia Botulinum Toxin

Elderly w/ progressive asymmetrical extrapyramidal rigidity, w/ signs of corticospinal disease, dementia in late stage

Corticobasal Degeneration (CBD)

Early features of CBD

Asymmetrical clumsiness of limbs, rigidity & tremor “Alien hand”

Essential feature of CBD in pathologic exam

Neuronal achromasia in posterior frontal & parietal neurons \*\*\* Asymmetry of degeneration too

Most important abnormal gene in Dystonia Musculorum Deformas

DYT1 (TOR1A) producing Torsin A

T/F. In general, more restricted types of Torsion dystonia have later onset and milder, slowly progressive & involves axial & distal region alone

TRUE

General Rule for inherited vs sporadic torsion dystonia

* Inherited (DYT1): early onset, begins one limb then genarlized * Sporadic: common dystonia, adult onset, craniocervical or another region, does NOT generalized

Cardinal feature of severe dystonia in Torsion dystonia

Simultaneous contractions of antagonist & agonist muscles

Drugs used in torsion dystonia early in disease

L-dopa Bromocriptine CBZ DZP Anticholinergic Intrathecal baclofen Clonazepam; segmental myoclonus

Dystonia responsive in L-dopa w/ parkinsonism features. AD inheritance, w/ affectation in what chromosome\_\_\_\_\_, for protein\_\_\_\_\_ implicated for synthesis of tetrahydrobiopterin, cofactor of tyrosine hydroxlase

* Segawa Syndrome / Heriditary Dystonia Parkinsonism * Chromosome 19q (GCH1 gene) * GTP cyclohydroxylase-1

Onset of Segawa syndrome

Between 4-8 years old

3 groups for progressive cerebellar syndromes

* Spinocerebellar ataxia * Pure Cerebellar ataxia * Complicated cerebellar ataxia

General rule for onset of chronic progressive ataxia

Recessive type: early onset (before age 20) Dominant: late onset \*\*\*\*emphasize most have no family hx hence spontaneous mutation

Pattern of inheritance & chromosome implicated w/ Friedreich Ataxia

AR, chromosome 9q13-2

Mutation in Friedreich Ataxia

Expansion of GAA repeat coded for fraxatin

Mitochondrial protein matrix preventing intramitochondrial loading

Fraxatin

Spinocerebellar ataxia, neuropathy, cardiomyopathy arrhythmia, kyphoscoliosis and hammertoes occurring in TEENS (AR)

Friedreich’s ataxia

Spinocerebellar ataxia, neuropathy, cardiomyopathy arrhythmia occurring in CHILD (AR) related to lack of vitamin

Variant of Friedreich Ataxia

Prototype of all forms of progressive spinocerebellar ataxias

Friedreich ataxia

Always the initial symptom of Friedreich’s ataxia

Ataxia

Characteristic foot deformity in Friedreich’s ataxia

Hammertoes

Notable feature in Friedreich’s ataxia hence requires careful cardiologic assessment

Cardiomyopathy

T/F. Tendon reflexes are intact in Friedreich’s ataxia

FALSE. Nearly all are abolished especially in later stages

In Friedreich’s ataxia, CT or MRI may show:

Cerebellar atrophy and spinal cord is small

Neuropathologic changes in Friedreich’s ataxia

Spinal cord thin: due depleted myelinated fibers of posterior column, corticospinal tract, spinocerebellar tract Moderate neuronal loss of dentate nuclei, middle & superior cerebellar peduncles Amyotrophy of intrinsic muscles of foot & kyphoscoliosis

Treatment used in Friedreich’s ataxia to: * Modify cerebellar symptoms * Reduced progression of LVH, arrhythmia, and sudden death

* 5-hydroxytryptophan * Idebenone

Ataxia related to degeneration of cerebellum and brainstem w/ sparing of spinal cord

Predominantly Cerebellar Hereditary & Sporadic Ataxia (Holmes Type)

Progressive ataxia, hesitant speech, rare nystagmus and preserved intelligence occurring at fourth decade

Predominantly Cerebellar Hereditary & Sporadic Ataxia (Holmes Type)

Pathologic changes in Predominantly Cerebellar Hereditary & Sporadic Ataxia (Holmes Type)

Symmetrical atrophy of cerebellum mainly the vermis and anterior lobe

Disease that is similar in terms of clinical and pathologic changes in Predominantly Cerebellar Hereditary & Sporadic Ataxia (Holmes Type)

Alcoholic cerebellar degeneration

Ataxia caused by extended trinucleotide repeat of CGG (50-200 rpts) in FMR1 gene, and breakage of X-chromosome, associated w/ developmental delay T2 hyperintensities in cererbellar peduncles are characteristic

Fragile X Tremor-Ataxic Permutation Syndrome

SCA w/ that AD inheritance initially observed among Azoreans presenting as ataxia, spasticity, neuropathy and EXTRAPYRAMIDAL features

Machado-Joseph Disease (SCA3)

* Cerebellar ataxia w/ choreoathetosis & dystonia * Gene defect is unstable CAG trinucleotide repeat coding for protein

* Dentatorubropallidoluysian (DRPLA) * Atrophin

Paroxysmal ataxia, where vertigo is the prominent symptom and responsive to acetazolamide \_\_\_\_\_\_\_ gene on Chrom 19

Episodic Ataxia-2 Calcium channel

Paroxysmal ataxia precipitated by exercise and presence of myokimia caused by _______ gene on Chrom 12

Episodic Ataxia-1 Potassium channel

Relatively pure form of myoclonus w/o ataxia that is autosomal dominant responsive w/ clonazepam, VPA, and 5-hydroxytryptophan

Hereditary Benign Essential Myoclonus

The gene mutation in ALS in familial cases

SOD1 gene (superoxide dismutase)

Earliest manifestation of LMN in ALS is

Volitional cramping

ALS triad

* Atrophic weakness of hands & forearms/ fasciculations * Spasticity & generalized hyperreflexia * Absent sensory changes

T/F. Fasciculation is almost always the sole presenting feature of ALS

FALSE. Almost NEVER.

Half of patient succumb in _____ years And 90 % in ______ years

* 3 years * 6 years

Purely LMN syndrome common in men, that has slower progression w/ 15 years survival

Progressive muscular atrophy

The main disease to be distinguished from Progressive muscular atrophy

Immune-mediated motor neuropathy

Distinguishing feature of Primary Lateral Sclerosis from ALS,

Purely UMN progression for 3 years w/o evidence of LMN

EMG diagnostic criteria for ALS

Denervation demonstrated in at least 3 limbs May also include paraspinal or genioglossus denervation

Treatment for ALS that may slow progression and add only 3 MONTHS of life

Riluzole

T/F. The amount of SMN 2 protein determines the severity and time of onset of disease.

TRUE. Less SMN2 copies more severe

SMA that manifest upon birth as neonatal hypotonia, due to 2 copies of SMN2 protein

SMA I (Infantile, Werdnig-Hoffmann)

SMA w/ delayed motor development and proximal leg weakness, that is slowly progressive usually beyond 1 year old

SMA III (W-K-W disease)

Distal muscular atrophy w/ prominent bulbar signs, associated w/ gynecomastia, oligospermia and diabetes Genetic defect is CAG expansion in the gene coding ______ at short arm of X-chromosome

* Kennedy Syndrome * Androgen receptor

Progressive bulbar palsy in childhood that is autosomal recessive associated w/ mutation in riboflavin receptor

Fazio-Londe Syndrome

Progressive visual loss w/ evident optic atrophy related to mitochondrial disease. Onset is 18-25 y/o

Leber Heriditary Optic Atrophy

Progressive visual loss initially w/ nyctalopia, w/ triad of ophthalmoscopic finding of pigmentary deposits in bone corpuscles, attenuated vessels and pallor optic disc.

Retinitis pigmentosa

Inverse of retinitis pigmentosa, where progressive visual loss by macular degeneration w/ pathognomonic “dark choroid” pattern

Stargardt disease