inherited neurodegenerative disorders NIMS HOSPITAL,HYDERABAD

1. ADULT NEURODEGENERATIVE DISORDERS
BY DR.SRUTHI MEENAXSHI

2. NEURODEGENERATIVE disorders, which
are chronic and progressive, are characterized
by selective and symmetric loss of neurons
in motor, sensory, or cognitive systems.

3. Martin JB. N Engl J Med .
Classification of Inherited Neurodegenerative
Disorders.

4.  Alzheimer’s disease usually begins
in the seventh to ninth decades of
life, but an early-onset familial
form is now well recognized.
 The neuropathological hallmarks
of neurofibrillary tangles and
senile plaques were described by a
German psychiatrist,Alois
Alzheimer, in 1907.
 Neurofibrillary tangles are
aggregations of the microtubular
protein tau, which is
hyperphosphorylated.

5.  Senile (neuritic) plaques result from the
accumulation of several proteins and an
inflammatory reaction around deposits of b-
amyloid.
 Degenerating nerve terminals in the plaques
also contain tau.
 As these cellular changes progress, neurons
are lost in the hippocampus, entorhinal
cortex, and association areas of the
neocortex.

9.  Several illnesses characterized by dementia and often called Pick’s
disease are associated with selective loss and atrophy of neurons
in the frontal and temporal lobes
 The typical initial clinical findings are abnormal behavior without
memory loss, followed by progressive dementia and, in some
patients, parkinsonian symptoms of bradykinesia and rigidity.
 Brain imaging reveals severe frontal and temporal atrophy caused
by neuronal loss in the cerebral cortex and amygdala, with less
marked changes in the hippocampus.
 Tau-positive inclusions are found in neurons and glial cells, but
senile plaques are not present.

10.  Although usually sporadic in occurrence, a rare autosomal dominant inherited
form of frontotemporal dementia associated with Parkinson’s disease was
linked to the same region of chromosome 17q21– 22 as the gene for tau.
 Analysis of the tau gene in one family with frontotemporal dementia revealed
nine polymorphisms, of which eight could be discounted because of their
occurrence in normal subjects.
 One variation, however, Val279Met, was linked to the disease.
 Another mutation involves an alternative splice site downstream from
exon10, six different mutations in this region have been identified in 13 families
with frontotemporal dementia and parkinsonism.
 These findings suggest that errors in the splicing of exon 10 may result in the
production of tau molecules that bind abnormally to microtubules.
 This error may cause tau to polymerize into neurofibrillary tangles.

13.  Eight neurologic disorders are caused by an increase
in the number of CAG repeats that encode expanded
sequences of glutamine residues .
 These disorders are characterized by autosomal
dominant or X-linked inheritance, onset in midlife, a
progressive course, anticipation (a tendency toward
earlier onset in successive generations),
preponderance of unstable repeats from the paternal
chromosome, and correlation of the number of CAG
repeats with the severity of disease and the age at
onset

15.  Huntington’s disease is an autosomal dominant disorder with high penetrance.
 The characteristic findings of progressive chorea and dementia are caused by
severe neuronal loss, initially in the neostriatum and later in the cerebral cortex.
 Huntington’s disease was linked initially to chromosome 4p16.3,8 in which one
gene, initially labeled IT15 and now called HD, was found to contain an unstable
CAG repeat in the open reading frame of its first exon.
 Normal subjects have a median of 19 CAG repeats (range, 11 to 34), whereas
nearly all patients with Huntington’s disease have more than 40.
 Unstable or dynamic mutations have been identified in a few families, in which
one parent has 34 to 38 CAG repeats and the progeny have more than 40.
 The HD gene encodes a protein named huntingtin

18.  The Spinocerebellar ataxias (SCA) are a
subset of hereditary cerebellar ataxias that
are autosomal dominantly transmitted.
 They are progressive neurodegenerative
diseases that share the clinical features of
ataxia, which arise from the progressive
degeneration of the cerebellum but can also
affect other connected regions,including the
brain stem

19.  They are ahighly heterogenous group of
disorders with a complex genotype–
phenotype spectrum;many SCAs are caused
by CAG nucleotide repeat expansions that
encode polyglutamine,and therefore,involve
the toxic polyglutamine protein (polyQ)

20. Spinocerebellar ataxia – An update ,Sullivian et al, Journal of Neurology
https://doi.org/10.1007/s00415-018-9076-4

21. Spinocerebellar ataxia – An update ,Sullivian et al, Journal of Neurology
https://doi.org/10.1007/s00415-018-9076-4

22. Spinocerebellar ataxia – An update ,Sullivian et al, Journal of Neurology
https://doi.org/10.1007/s00415-018-9076-4

27.  Prion diseases have a broad spectrum of clinical manifestations, including dementia,
ataxia, insomnia, paraplegia, paresthesias, and deviant behavior.
 Neuropathological findings range from an absence of atrophy to widespread atrophy, from
minimal to widespread neuronal loss, from sparse to widespread vacuolation or spongiform
changes, from mild to severe reactive astrocytic gliosis, and from an absence ofPrPamyloid
plaques to an abundance of plaques.
 None of these findings except the presence of PrP amyloid plaques is unequivocally
diagnostic of a prion disease.The sporadic form of Creutzfeldt–Jakob disease, which is
typically manifested as dementia and myoclonus, accounts forapproximately 85 percent of
all cases of prion disease inhumans,whereas infectious and inherited prion diseases
account for the rest.

28.  Familial Creutzfeldt–Jakob disease, Gerstmann–
Sträussler–Scheinker disease,and fatal familial
insomnia are all dominantly inherited prion diseases
caused by mutations in the prion protein gene PRNP
 Experiments that showed transmission of these
diseases by filtrates of brain from familial cases were
wrongly attributed to a virus.
 There is no Creutzfeldt– Jakob disease virus, and
familial prion diseases are caused by mutations in
PRNP

30.  Friedreich's ataxia is an autosomal recessive disorder caused by an
increase in the number of trinucleotide GAA repeats within the
first intron of the FRDA gene on chromosome 9 that encodes the
protein frataxin
 The disease is characterized clinically by the onset in the first two
decades of life of limb ataxia, cerebellar dysarthria, a lack of deep-
tendon reflexes, pyramidal signs, and sensory loss.
 Most patients have skeletal deformities and hypertrophic
cardiomyopathy.
 They also have an increased incidence of blindness, deafness, and
diabetes mellitus, suggesting that the disorder is systemic and is
not limited to the nervous system.

31.  Friedreich's ataxia is the most common of the hereditary
ataxias
 The locus was mapped to chromosome 9 in 1988, and
the FRDA gene was cloned in 1996.
 More than 95 percent of patients with classic Friedreich's
ataxia are homozygous for the increase in GAA repeats,
but a few have a combination of an increase in GAA
repeats in one allele and a point mutation in the other
allele, confirming that Friedreich's ataxia is a loss-of-
function disorder.
 The disorder may be caused by interference by the
intronic GAA repeat with transcription of the FRDA gene

32.  The neural pathways affected in Friedreich's ataxia
are those associated with large neuronal cell bodies
and extensive axon elongations — the long tracts of
the dorsal columns, pyramidal system, and peripheral
nerves.
 Many of the clinical manifestations of the disease are
mimicked by disorders of vitamin E metabolism.
 In affected patients, the concentrations of a partially
degraded, 180-kd form of frataxin are abnormally low
in muscle, cerebellar cortex, and cerebral cortex, and
the frataxin is closely associated with mitochondria.

33.  Frataxin contains 210 amino acids, and its N-
terminal region contains an α-helix that might
target the protein to mitochondria.
 The current hypothesis is that frataxin is a
mitochondrial protein important for normal
production of cellular energy.
 A defect in its action may result in abnormal
accumulation of iron in mitochondria,followed
by the death of the neurons that are most
vulnerable to this abnormality.

35.  Parkinson's disease is the second most common
neurodegenerative disorder after Alzheimer's disease, with a
prevalence of 2 percent among people over the age of 65 years.
 The characteristic symptoms of rigidity, bradykinesia, and tremor
are associated with loss of cells in the substantia nigra and
depletion of dopamine in the striatum.
 Large intracytoplasmic inclusions called Lewy bodies are the
pathological hallmark of the disease, occurring predominantly in
the melanin-containing neurons of the substantia nigra.
 Linkage data in a subgroup of families with autosomal dominant
Parkinson's disease identified a disease locus on chromosome
4q21–23 and mutations in the gene for a synaptic protein, α-
synuclein.

38.  In patients with both inherited and sporadic Parkinson's disease, the
Lewy bodies contain α-synuclein, ubiquitin, and proteasomal subunits.
 Mutations in another protein, ubiquitin carboxy-terminal hydrolase,
have also been reported to cause familial Parkinson's disease.
 These mutations are hypothesized to lead to aberrations in the
proteolytic pathway and to aggregation of proteins as Lewy bodies.
 In another common condition, diffuse Lewy body disease (also called
Lewy body dementia), Lewy bodies are widely distributed in cortical
neurons.
 The Lewy bodies in this condition are identical biochemically to those in
sporadic or inherited Parkinson's disease.

39.  Motor neurons extend from the brain stem throughout the spinal cord,
forming the final common pathway for motor control.
 Lower motor neurons innervate muscles, and upper motor neurons carry
impulses to lower motor neurons for voluntary muscle movements.
 Motor-neuron axons are among the longest in the nervous system.
 In normal persons, they are capable of surviving more than 100 years.
 Many inherited and sporadic misadventures may befall them, giving rise
to muscle atrophy and weakness, and with the death of upper motor
neurons, increased muscle tone (spasticity), hyperreflexia, and extensor
plantar responses.

40.  The most common motor-neuron disorder is amyotrophic lateral
sclerosis, which usually begins in the fifth and sixth decades of life.
 In a typical patient, muscles innervated by both brain stem and spinal
cord atrophy as lower motor neurons die, although those that control
eye movements and bowel and bladder function are spared.
 The illness is usually sporadic, but in 1 to 10 percent of patients it is
familial, being inherited as an autosomal dominant trait.
 The inherited and sporadic forms are indistinguishable clinically.
 In both forms the prognosis is grave, with death occurring in three to five
years in 95 percent of patients.
 Neuropathological studies show loss of motor neurons throughout the
neuraxis.
 The death of neurons is preceded by perikaryal shrinkage, the formation
of webs of ubiquitin-positive threads, and axonal swellings that stain for
ubiquitin and for α-synuclein.

41.  The cause of motor-neuron loss in
amyotrophic lateral sclerosis remains
unknown, but a subgroup of patients with the
familial form (less than 20 percent) have
mutations in the superoxide dismutase type 1
(SOD1) gene on chromosome 21, which
encodes a protein involved in the regulation
of intracellular free radicals.

43.  A consideration of motor-neuron disorders should not be limited
to those with an onset in adult life.
 There are several inherited autosomal recessive disorders of
childhood, grouped together as spinal muscular atrophy, in which
lower motor neurons are predominantly affected.
 Two genes on chromosome 5q13 are associated with the disorder.
 The most important of these genes is one that encodes a novel
protein, survival motor neuron, which appears to act by
influencing the metabolism of messenger RNA.
 The survival motor neuron (SMN) gene is duplicated on
chromosome 5q, with one copy centromeric and the other
telomeric in position.
 The two copies differ only by single base pairs in exons 7 and 8.

45.  Approximately 95 percent of patients with spinal muscular atrophy have
deletions in the telomeric SMN gene
 Others have short deletions or missense mutations.
 There may be a balance between the numbers of copies expressed by the
centromeric and telomeric SMN genes.
 In some mildly affected patients, there is a complete absence of
expression of the telomeric SMN gene but overexpression of the
centromeric SMN gene.
 The role of another gene in the 5q region that encodes a protein called
neuronal apoptosis inhibitory protein (based on its homology with
certain viral antiapoptotic proteins) remains controversial.
 It may be neuroprotective in the disorder, resulting in less severe
symptoms when fully expressed, since it seems to be so in some patients
with telomeric SMN mutations.

49.  Spinal and bulbar muscular atrophy is an X-
linked disorder with an onset in midlife in
which increased numbers of CAG repeats are
found in the androgen receptor gene
 Affected patients have symptoms of motor-
neuron loss throughout the neuraxis, caused
presumably by selective effects of the CAG
repeats in neurons rich in androgen
receptors.

50.  Familial spastic paraparesis is inherited as either an
autosomal dominant or X-linked condition that selectively
affects upper motor neurons.
 Linkage studies point to genetic heterogeneity with loci
on chromosomes 2p, 14q, and 15q.
 One form is reported to be associated with an increased
number of CAG repeats in a gene on chromosome 2p21–
24, but this association has not been confirmed and the
gene product has not been identified.
 The gene for an autosomal recessive variant of familial
spastic paraparesis encodes a protein, paraplegin.

54.  PROGRESSIVE NEUROLOGICALAND
MENTAL DETERORIATION

56.  Leukodystrophies currently are defined as
genetically determined disorders that
primarily affect the white matter of the
central nervous system, regardless of the
structural white matter component,
molecular process, patient age group, and
disease course involved.
 Genetic testing is of paramount importance

57.  Leukodystrophies usually affect children, but
in the last several decades, many instances of
adult leukodystrophies have been reported in
the medical literature.
 Because the clinical manifestation of these
diseases can be nonspecific, MRI can help
with establishing a diagnosis.

61.  Metachromatic leukodystrophy is an
autosomal recessive lysosomal condition
due to arylsulfatase A (ARSA) gene
mutations, resulting in deficiency of the
enzyme arylsulfatase A (ASA) that leads to
accumulation of 3-O-sulfogalactosylceramide
(sulfatide) in oligodendrocytes, Schwann
cells, and some neurons

62.  Adults account for approximately 20% of
patients with metachromatic leukodystrophy.
 The initial symptoms are often behavioral and
psychiatric changes, followed by a slow decline
in memory and intellectual abilities.
 Later, the onset of motor symptoms including
spastic paraparesis and cerebellar ataxia and
peripheral neuropathy occur.

63.  MRI findings consist of confluent, symmetricT2
hyperintensity in the frontal or periventricular
white matter (Fig 6).
 The subcortical U fibers are spared, and
frequently some frontal predominance is
present in patients with adult-onset
metachromatic leukodystrophy.
 Loss of white matter volume results in brain
atrophy in the late stages of the disease

65.  Niemann-Pick type C disease (NPC) is a rare, neurovisceral, autosomal recessive
disease, with an extremely heterogeneous clinical presentation.
 It is characterized by a wide range of symptoms that are not specific, such as
neurological, systemic or psychiatric symptoms.
 The adult form of the disease concerns a small proportion (5 %) of the people
affected and is usually expressed as a neurological form.
 A variety of progressive and disabling symptoms are encountered, mainly
cerebellar signs (cerebellar ataxia, impaired gait, dysarthria), but also movement
disorders, cataplexy, seizures and dysphagia.
 Patients face constant cognitive deterioration, which can result in severe
dementia.
 Abnormal saccadic eye movement is often the first manifestation of the disease.
 Supranuclear gaze palsy is considered to be a specific sign and should be
systematically searched for.

66.  In terms of systemic signs, the usual infantile hepatosplenomegaly is
very fickle in the adult form; if present, it is usually asymptomatic.
 Non-specific psychiatric symptoms are often associated with NPC
disease.
 For one third of cases, it can also express as an isolated psychiatric-
disorder form, such as schizophrenia-like psychosis (paranoid delusions,
auditory hallucinations, interpretative thoughts, and disorganization),
depression, bipolar disorder, obsessive-compulsive behaviour and
behavioural problems (sleep disorders, hyperactivity, agitation,
aggressiveness or self-mutilations).
 This psychiatric overview is mostly atypical and is accompanied by visual
hallucinations, confusion, symptom fluctuations, treatment resistance or
aggravation with neuroleptic drugs, catatonia, progressive cognitive
decline, but also seizures.

67.  NPC diagnosis is based on a filipin test on a fibroblast culture from a skin
biopsy and also on a sequencing of the NPC1 and NPC2 genes.
 Routine laboratory biochemistry profiles are generally normal.
 The early diagnosis is fundamental to deploy the best follow-up care.
 The patient should therefore be in contact with a reference centre. Until
recently, NPC treatment consisted in supportive therapies and
symptomatic drugs, useful, however, with variable efficacy.
 The recent discovery of a medicine called Miglustat (N-
butyldeoxynojirimycin; NB-DJN; Zavesca(®),Actelion Pharmaceuticals
Ltd.) which improves the disease evolution, should encourage
psychiatrists to look for it in every atypical psychosis.

68.  3-Hydroxy-3-methylglutaric aciduria (3-HMG, OMIN 246450) is a
rare autosomal recessive metabolic disorder caused by a
deficiency of 3-hydroxy-3-methylglutaryl-CoA lyase, a key enzyme
in leucine metabolism and ketone body synthesis.
 Acute episodes of 3-HMG may be triggered by fasting or infection,
and symptoms include vomiting, diarrhea, lethargy and
hypotonia.
 If left untreated, prolonged hypoglycemia and metabolic acidosis
may cause breathing problems, seizures, and coma.
 In addition, 3-HMG is associated with damage to the central
nervous system, and there are several reports of white matter
abnormality or cerebral atrophy

69.  Wilson disease is an autosomal recessive condition, although it was not until 1985 that it was
linked to chromosome 13.
 In 1993, 2 separate groups described mutations in the ATP7B gene in patients with Wilson
disease.
 More than 500 ATP7B mutations have now been identified
(http://www.wilsondisease.med.ualberta.ca/database.asp).
 Individual gene mutations have not been reliably associated with different presentations of
Wilson disease although there is some evidence that truncating mutations may be associated
with earlier onset than missense mutation and patients with frameshift mutations may be more
likely to develop neurologic symptoms.
 Interestingly, there are case reports of monozygotic twins who are phenotypically discordant for
Wilson disease.
 This finding strongly suggests there must be at least some contribution of environmental and
epigenetic factors contributing toWilson disease

70.  The copper metabolism disorder Wilson's disease was first
defined in 1912.
 Wilson's disease can present with hepatic and neurological
deficits, including dystonia and parkinsonism.
 Early-onset presentations in infancy and late-onset
manifestations in adults older than 70 years of age are
now well recognised.
 Direct genetic testing for ATP7B mutations are
increasingly available to confirm the clinical diagnosis of
Wilson's disease

73.  Homocystinuria caused by cystathionine β-
synthase (CBS) deficiency is characterized by
involvement of the eye (ectopia lentis and/or
severe myopia), skeletal system (excessive
height, long limbs, scolioisis, and pectus
excavatum), vascular system
(thromboembolism), and CNS (developmental
delay/intellectual disability).
 All four ‒ or only one ‒ of the systems can be
involved; expressivity is variable for all of the
clinical signs.

74.  Two phenotypic variants are recognized, B6-responsive homocystinuria
and B6-non-responsive homocystinuria.
 B6-responsive homocystinuria is usually milder than the non-responsive
variant.
 Thromboembolism is the major cause of early death and morbidity. IQ in
individuals with untreated homocystinuria ranges widely, from 10 to 138.
 In B6-responsive individuals the mean IQ is 79 versus 57 for those who are
B6-non-responsive.
 Other features that may occur include: seizures, psychiatric problems,
extrapyramidal signs (e.g., dystonia), hypopigmentation of the skin and
hair, malar flush, livedo reticularis, and pancreatitis.

75.  The cardinal biochemical features of
homocystinuria include markedly increased
concentrations of plasma total homocysteine
and methionine.
 The diagnosis can be substantiated by
detection of biallelic pathogenic variants
in CBS, the gene encoding cystathionine β-
synthase.

76.  Prevention of primary manifestations: Individuals
are treated to maintain normal or near-normal
plasma total homocysteine concentrations using
vitamin B6 (pyridoxine) therapy (if shown to be
B6 responsive), a methionine-restricted diet, and
folate and vitamin B12 supplementation. Betaine
therapy is usually added to the therapeutic
regimen; in adolescents and adults, betaine may
be the major form of treatment, but it is
preferable to remain on life-long metabolic diet.

78.  The neuronal ceroid lipofuscinoses (NCLs) are at least 13 distinct progressive
neurodegenerative disorders unified by the accumulation of lysosomal auto-
fluorescent material called lipofuscin
 The only form that occurs via autosomal-dominant inheritance exhibits adult
onset and is sometimes referred to as Parry type NCL.
 The manifestations may include behavioral symptoms followed by seizures,
ataxia, dementia, and early death
 Mutations in the gene DNAJC5 that codes for the presynaptic co-chaperone
cysteine string protein-α (CSPα) were recently reported in sporadic adult-onset
cases and in families with dominant inheritance.
 The mutant CSPα protein may lead to disease progression by both loss and gain
of function mechanisms.
 Iron chelation therapy may be considered as a possible pharmaceutical
intervention

79.  Clinically, most of these patients first presented with seizures. In our experience, other milder
features such as behavioral changes, progressive tremor, myoclonus, memory loss, and frequent
falls may precede the onset of seizures.
 The age of onset of clinical seizures ranges from mid-20s to mid-40s.
 All reported patients had abnormal EEG readings at the time of their initial clinical
manifestations.
 The EEG abnormalities at earlier stages of the disease showed predominance of diffuse theta and
delta slow waves during wakefulness, intermittent delta activity, and generalized spike-wave and
poly spike-wave complexes indicative of epileptogenic potential.
 These changes become more prominent during the disease progression. After the onset of the
seizures, there is slow, progressive cognitive decline, ataxia, memory loss, and speech
impairment.
 Some patients show signs of depression.
 Age at death typically ranges from late 30s to 60 years and appears to be dependent upon the
age of onset of the seizures.The usual cause of death is severe neurological compromise and
resulting multi-organ failure

80.  Alexander Disease.—Alexander disease is the result of
an autosomal dominant mutation inthe glial fibrillary
acidic protein (GFAP) gene.
 These mutations usually are de novo but may be
hereditary in patients with adult-onset disease.
 This condition is characterized pathologically by
diffuse Rosenthal fiber accumulation in astrocyte
cytoplasms.
 Molecular testing is diagnostic, and a brain biopsy is
no longer required to confirm the diagnosis (37,39).

81.  The clinical presentation includes slowly progressive bulbar dysfunction
(dysphagia, dysarthria, and dysphonia), pyramidal signs, and ataxia, with
normal cognitive and intellectual functions.
 When present, palatal myoclonus is suggestive of this diagnosis
(8,40,41).
 MRI findings in patients who develop Alexander disease in adulthood
differ substantially from those of the early-onset form of the disease (Fig
9).
 White matter signal intensity abnormalities (increased signal intensity on
T2-weighted and FLAIR MR images) and mild to severe atrophy of the
medulla oblongata extending caudally to the upper cervical spinal cord
are the hallmarks of this condition.
 Middle cerebellar peduncle signal intensity abnormalities also may be
observed, and patchy enhancement may be present in affected regions.

83.  Cerebrotendinous xanthomatosis (CTX) is a treatable autosomal
recessive disorder and is characterized as a lipid storage disease
caused by a mutation of the cytochrome P450 family 27 subfamily
A member 1 (CYP27A1) gene, which leads to a deficiency of the
mitochondrial enzyme 27-hydroxylase.
 This enzyme catalyzes one of the first steps in the metabolism of
sterols. CTX results in the development of a tendinous xanthoma,
early cataracts, diarrhea, and leukoencephalopathy.
 If left untreated, patients might develop progressive dementia
and psychiatric symptoms
 The earliest and most relevant MRI features of CTX are
involvement of the cerebellar white matter (Fig 11).

85.  High signal intensity in the deep periventricular white
matter and low or high signal intensity in the dentate
nucleus onT2-weighted MR images is characteristic.
T2- hypointense areas may be observed and probably
represent hemosiderin deposition
 MR spectroscopy in patients with CTX shows
increases in lactate and lipid peaks and a decreased N-
acetyl aspartate peak, mainly in the cerebellum.The
presence of lipid peaks is reasonable because CTX is a
lipid storage disease.

86.  Krabbe Disease.—Less commonly, Krabbe
disease can manifest as diffuse
periventricular white matter involvement

88.  L-2-hydroxyglutaric aciduria is a rare neurometabolic disorder with
autosomal recessive inheritance (L-2-hydroxyglutarate dehydrogenase
[L2HGDH] gene) that is characterized by leukoencephalopathy that
predominantly affects subcortical white matter (Fig 8) (14)
 . Patients initially may appear asymptomatic or may have a static
encephalopathy
 .The neurologic symptoms are progressive and include cerebellar ataxia
and intellectual decline
 . Hearing loss is another possible symptom of the disease.
 In certain patients, these features become apparent only in adulthood.
Increased L2-hydroxyglutaric acid in urine is diagnostic (37)

89.  . MRI in patients with L-2-hydroxyglutaric aciduria shows
predominant subcortical white matter involvement,
initially focal and evolving to become confluent.
 Periventricular white matter is spared. Increased signal
intensity onT2-weighted or FLAIR MR images may be
observed in the globus pallidus, and less importantly, in
the caudate nucleus and putamen, with symmetric
distribution.
 These same signal intensity abnormalities also may be
observed in the dentate nucleus (38)

91.  afora disease (LD) is an autosomal recessive progressive
myoclonus epilepsy due to mutations in the EPM2A (laforin) and
EPM2B (malin) genes, with no substantial genotype-phenotype
differences between the two.
 Founder effects and recurrent mutations are common, and mostly
isolated to specific ethnic groups and/or geographical locations.
 Pathologically, LD is characterized by distinctive polyglucosans,
which are formations of abnormal glycogen.
 Polyglucosans, or Lafora bodies (LB) are typically found in the
brain, periportal hepatocytes of the liver, skeletal and cardiac
myocytes, and in the eccrine duct and apocrine myoepithelial cells
of sweat glands.

92.  With the exception of a few missense mutations LD is clinically homogeneous,
with onset in adolescence.
 Symptoms begin with seizures, and neurological decline follows soon after.
 The disease course is progressive and fatal, with death occurring within 10 years
of onset.
 Antiepileptic drugs are mostly non-effective, with none having a major influence
on the progression of cognitive and behavioral symptoms.
 Diagnosis and genetic counseling are important aspects of LD, and social
support is essential in disease management.
 Future therapeutics for LD will revolve around the pathogenesics of the disease.
 Currently, efforts at identifying compounds or approaches to reduce brain
glycogen synthesis appear to be highly promising.

94.  GM1 gangliosidosis is a rare disease that could manifest either during
infancy (infantile form-type 1), as a juvenile (type 2), or in adulthood
(type 3).
 There is a deficiency of the enzyme acid -galactosidase in both nervous
and skeletal systems, but when it involves the skeletal system alone, it is
called Morquio’s disease.
 The adult form (type 3) typically presents during childhood or
adolescence as a slowly progressive dementia with prominent
parkinsonian features and extrapyramidal disease, particularly dystonia.
 Marked phenotypic variability may occur.Age at death may vary greatly.
 Nervous system involvement in infantile and juvenile forms is
generalized, but is localized in the adult form.

95.  Similarly, skeletal involvement is generalized in the infantile form
but localized in late infantile and adult forms of the disease.
 Pathology in adult (type 3) GM1 gangliosidosis is localized to basal
ganglia with prominent involvement of caudate, putamen, and, to
a lesser degree, amygdala and globus pallidum.
 Dystonia thus is a major neurological manifestation in adults.
 Adult (type 3) form of GM1 gangliosidosis shows higher residual
activities of enzyme -galactosidase than infantile or juvenile
forms2 and has the I51T mutation

97.  Neurodegeneration with brain iron accumulation
(NBIA) comprises a clinically and genetically
heterogeneous group of disorders affecting children
and adults.
 These rare disorders are often first suspected when
increased basal ganglia iron is observed on brain
magnetic resonance imaging.
 For the majority of NBIA disorders the genetic basis
has been delineated, and clinical testing is available.


98.  The four most common NBIA disorders include
1. pantothenate kinase-associated neurodegeneration
(PKAN) due to mutations in PANK2,
2. phospholipase A2-associated neurodegeneration
caused by mutation in PLA2G6,
3. mitochondrial membrane protein-associated
neurodegeneration from mutations in C19orf12,
4. and beta-propeller protein-associated
neurodegeneration due to mutations inWDR45.

99.  The ultrarare NBIA disorders are caused by
mutations in CoASY, ATP13A2, and FA2H
(causing CoA synthase protein-associated
neurodegeneration, Kufor-Rakeb disease,
and fatty acid hydroxylase-associated
neurodegeneration, respectively).
 Together, these genes account for disease in
approximately 85% of patients diagnosed
with an NBIA disorder