Page 884 - Motor Disorders Third Edition
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866 / chapter 57 family of CLN4B was characterized by seizures, dementia,
imbalance, would not explain white matter destruction; and myoclonus, and several individuals had parkinsonism
however, mitochondrial abnormalities, so noted in the prior to known molecular genetic localization to DNAJC5
liver of one patient with WD (46), suggested a contribu- (50). The same investigators (51) identified a heterozygous
tion of mitochondrial injury to other organs, including mutation in the DNAJC5 gene in a Czech family with auto-
the brain. Mutation of the WD protein, that results in somal dominant ACLN manifesting progressive confusion
accumulation of intracellular copper and lead to oxidative and dementia as well as frequent medically refractory gen-
attacks and damage within target tissues, is suggested by eralized seizures. Brain MRI in the proband, age 38 years,
the correlation between severity of the neuropathological showed prominence of cortical sulci and cerebellar folds,
findings and cerebral copper content (47). and mild lateral ventricular enlargement consistent with
diffuse cerebral and cerebellar atrophy. Concurrent neuro-
ADULT NEURONAL CEROID psychiatric testing showed a full-scale intelligence quotient
LIPOFUSCINOSIS (IQ) of 73 with ensuing ataxia and myoclonus. Frontal lobe
brain biopsy showed numerous neurons containing homog-
This disorder belongs to the neuronal ceroid-lipofuscinoses enous eosinophilic material that stained intensely with the
(NCL) group of inherited neurodegenerative lysosomal- periodic acid-Schiff reaction and was found to be auto-
storage disorders categorized by patterns of intracellu- fluorescent with multiple neurons distended by granular
lar accumulation of autofluorescent lipopigment storage osmiophilic deposits by ultrastructural examination. While
material, age at onset, and order of appearance of common challenging and often requiring invasive brain biopsy, avail-
clinical features from infancy to adulthood, including pro- able mutation screening for CLN4A and B should now be
gressive dementia, seizures, and visual failure (48), with considered as initial diagnostic steps in patients with sus-
each phenotype assigned a unique ceroid lipofuscinosis pected Kufs disease.
(CLN) gene symbol. Kufs disease or adult ceroid lipofus-
sinase (ACLN) presents in patients ranging from teenagers HUNTINGTON DISEASE
to persons greater than age 50 years, has a typical age at
onset of 30 years, and differs from other forms of NCL in This phenotypically heterogeneous autosomal dominant
preservation of vision due to lack of retinal involvement. disorder presents in previously healthy persons age five to
Until recently, brain biopsy was required to confirm the eight years, but mainly in the fourth to fifth decades of life,
diagnosis of ACLN because, unlike other forms of NCL with chorea, dystonia, incoordination, cognitive decline,
in which electron microscopy (EM) can be performed on and behavioral disturbances. The cause of the disorder is
heparinized whole blood lymphocytes and tissue biopsy of abnormally expanded trinucleotide CAG repeats in the
skin, conjunctiva, or other tissue, the characteristic lipopig- HTT gene located on chromosome 4p16.3 encoding hun-
ment in Kufs disease is largely confined to neurons. The tingtin. The detection of an expansion of 36 or more CAG
two clinical subtypes of Kufs disease, classically designated repeats in HTT in the setting of a positive family pedigree,
type A and B for the differing clinical presentation, have and characteristic clinical findings, makes the diagnosis
since been categorized by their respective CLN designa- essentially certain. The length of CAG repeats correlates
tions, CLN4A and CLN4B, allowing further separation by with an earlier age of onset, a cognitive behavioral presen-
mode of inheritance and causative genetic mutations, with tation, and an accelerated disease progression. Subcortical
minor phenotypic overlap. Kufs type A disease (CLN4A), cognitive dysfunction in HD, which typically spares long-
which displays autosomal recessive inheritance, is caused term memory but impairs executive functions such as orga-
by homozygous or compound heterozygous mutation at the nization, planning, checking, or adaptation of alternatives,
15q23 locus of the CLN6 gene encoding ceroid-lipofuscino- and delays the acquisition of new motor skills (52), wors-
sis neuronal protein 6, presents generally with progressive ens over time with speech deteriorating faster than com-
myoclonic epilepsy, whereas CLN4B, manifesting autoso- prehension. Unlike cognitive disturbances, psychiatric and
mal dominant inheritance, is due to heterozygous mutation behavioral involvement seen in 98% of patients, including
at the 20q13.33 locus of the DNAJC5 gene encoding cyste- depression, apathy, aggression and disinhibition, do not
ine-string protein alpha, presenting instead with dementia proceed in a stepwise progression along with worsening
and a variety of motor-system signs. Accordingly, among disease severity.
four families with Kufs disease for whom there was good
evidence of an autosomal recessive inheritance, three were Patients with juvenile HD (JHD), defined as onset before
affected by Kufs type A disease, presenting with tonic-clonic age 20 years (53), can have an insidious onset with nonspe-
seizures or action myoclonus, followed by ataxia, cogni- cific psychiatric and cognitive difficulties. Among a cohort
tive decline, or dementia (49). A four-generation Alabama of French JDH patients (54), the commonest signs at onset
