dementia

Spinocerebellar Ataxia 3

Clinical Characteristics
Ocular Features: 

External ophthalmoplegia in some form is usually present and there may be a supranuclear component.  Smooth horizontal movements are impaired and saccades are dysmetric.  Gaze-evoked nystagmus is a common finding.  The eyes are often described as 'bulging' and this has been attributed to eyelid retraction.  With time the abnormal saccadic movements slow resulting in ophthalmoparesis with restriction of upgaze.

Systemic Features: 

This form of spinocerebellar ataxia is considered to be the most frequent.  It is a progressive disease in all aspects which accounts for some of the considerable clinical heterogeneity reported.  Onset is likewise highly variable depending upon the number of repeats but usually sometime between the second to fifth decades.  In a large cohort of Azorean individuals the mean age of onset was reported to be 37 years.

An unsteady gait, dysarthric speech, general clumsiness, and diplopia are among the early symptoms.  Nystagmus, spasticity, and various autonomic signs including reduced bladder control may also be noted.  Chronic pain, sleep disturbances, impaired mental functioning, and memory deficits are often present and some authors have labelled these as indicative of dementia.

Virtually all clinical signs progress with ambulation difficulties requiring the need for assistive devices about a decade after the onset of disease.  Eventually signs of brain stem involvement appear with facial atrophy, perioral twitching, tongue fasciculations and atrophy, and dysphagia. Some degree of peripheral polyneuropathy with muscle wasting and loss of sensation are often present.  Tremors and other signs of Parkinsonism may be present.  Dystonic movements are often seen.

Imagining of the brain has revealed pontocerebellar atrophy and enlargement of the 4th ventricle but this is variable.  Nerve conduction studies documents involvement of the sensory nerves.  Neuropathologic studies show widespread neuronal loss in the CNS and spinal cord.

Genetics

This is considered to be an autosomal dominant disorder caused by an excess of heterozygous trinucleotide repeats in the ataxin3 gene (14q32) encoding glutamine.  The number in normal individuals is up to 44 repeats whereas patients with SCA3 have 52-86 repeats.  However, clinical signs of SCA3 have been found in patients with as few as 45 glutamine repeats.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

Physical and occupational therapy combined with regular exercise has been reported to slow the progression of symptoms.

References
Article Title: 

Machado-Joseph disease

Sudarsky L, Coutinho P. Machado-Joseph disease. Clin Neurosci. 1995;3(1):17-22. Review.

PubMed ID: 
7614089

Ataxia with Oculomotor Apraxia 4

Clinical Characteristics
Ocular Features: 

Oculomotor apraxia is usually noted after the ataxia and dystonia are apparent.

Systemic Features: 

The mean age of first symptoms is 4.3 years with dystonia being the first symptom.  Cerebellar ataxia is usually the second symptom to appear.  Cognitive impairment is present in most but not all patients with this condition.  This can progress to severe dementia in some individuals.  Dystonia may become attenuated with time.  Peripheral neuropathy with decreased vibration sense and areflexia is often present.  Cerebellar atrophy is present in all patients.

Motor difficulties such as weakness and muscle atrophy may lead to loss of independent mobility by the second to third decades.

Genetics

Homozygous or compound heterozygous mutations in the PNKP gene (19q13.33) are responsible for this disorder.

Mutations in this gene have also been associated with an infantile form of epileptic encephalopathy, microcephaly, and developmental delay (613402).

See also Ataxia with Oculomotor Apraxia 1 (208920) with hypoalbuminemia, Ataxia with Oculomotor Apraxia 2 (606002), and Ataxia with Oculomotor Apraxia 3 (615217).

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

There is no general treatment for this condition but physical therapy may be helpful in the early stages.

References
Article Title: 

MELAS Syndrome

Clinical Characteristics
Ocular Features: 

This progressive mitochondrial disorder primarily affects muscles and the CNS, including the visual system.  The pattern of ocular deficits is not consistent and those that are present are not specific, requiring the clinician to take the entire neurological picture into consideration.  Hemianopsia, cortical blindness and ophthalmoplegia may be present.  The ERG can show reduced b-wave amplitudes and VEPs may be absent.  The optic nerve head has been described as normal without the atrophy often seen with other mitochondrial disorders.  A pigmentary retinopathy may be present.

Systemic Features: 

The clinical picture is highly variable.  Most commonly patients have myopathy, encephalopathy, lactic acidosis, and stroke-like episodes.  The onset of symptoms is usually in the first two decades of life, most commonly consisting of headaches of sudden onset accompanied by vomiting and seizures.  The headaches may simulate migraines.  Weakness, lethargy, and apathy may be present early.  However, infants and young children may present with failure to thrive, developmental delay, and learning disabilities.  Neurosensory deafness is often seen and peripheral neuropathy is usually evident.  MRIs may show cerebellar hypoplasia and infarctions in the cerebral hemispheres.  Some patients have calcifications in the basal ganglia.  Patients may develop lactic acidosis.  Muscle biopsies often show ragged, red fibers.  The heart is commonly involved with both structural and rhythm defects.  Depending upon the degree and location of brain damage, patients may have hemiparesis, lethargy, ataxia, myoclonic jerks, cognitive decline, and dementia.  Morbidity and mortality are high.

Genetics

MELAS syndrome is a group of disorders caused by mutations in mitochondrial genes (at least 9 have been identified) that alter transfer RNA molecules resulting in disruption of intramitochondrial synthesis of proteins involved in oxidative phosphorylation pathways.  It is both clinically and genetically heterogeneous.  One can expect that any familial occurrence would result from maternal transmission but the occurrence of heteroplasmy results in considerable variability in the severity of clinical disease.

Treatment
Treatment Options: 

There is no effective treatment that prevents development of disease or that slows its progress.

References
Article Title: 

Wolfram Syndrome 2

Clinical Characteristics
Ocular Features: 

As in Wolfram syndrome 1, only insulin dependent diabetes mellitus and optic atrophy are essential to the diagnosis. The optic atrophy is progressive over a period of years and can be the presenting sign.  Its onset, however, is highly variable and may begin in infancy but almost always before the third decade of life.  The majority (77%) of patients are legally blind within a decade of onset.  The visual field may show paracentral scotomas and peripheral constriction.  Both VEPs and ERGs can be abnormal.  Diabetic retinopathy is uncommon and usually mild.

Systemic Features: 

The clinical features of this disorder are many and highly variable.  Sensorineural hearing loss, anemia, seizures, ataxia, and autonomic neuropathy are usually present. Respiratory failure secondary to brain stem atrophy may have fatal consequences by the age of 30 years.  A variety of mental disturbances including mental retardation, dementia, depression, and behavioral disorders have been reported.  The diabetes mellitus is insulin dependent with childhood onset.  Hydroureter is often present.

Diabetes insipidus may be present in patients with Wolfram syndrome 1 (222300) but has not been reported in patients reported with Wolfram syndrome 2.   Upper GI ulceration and bleeding were present in several individuals.

Genetics

This is an autosomal recessive disorder similar to Wolfram syndrome 1 (WFS1; 222300) but caused by mutations in the CISD2 gene (4q22-q24).  The gene codes for a small protein (ERIS) localized to the endoplasmic reticulum. It seems to occur less commonly than WFS1.

Some patients have mutations in mitochondrial DNA as the basis for their disease (598500).  Combined with evidence that point mutations at the 4p16.1 locus predisposes deletions in mtDNA, this suggests that at least some patients with Wolfram syndrome have a recessive disease caused by mutations in both nuclear and mitochondrial genes.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Treatment is supportive for specific organ disease.  Low vision aids may be helpful in selected individuals.

References
Article Title: 

Wolfram Syndrome 1

Clinical Characteristics
Ocular Features: 

Optic atrophy in association with diabetes mellitus is considered necessary to the diagnosis of Wolfram syndrome.  The optic atrophy is progressive over a period of years and can be the presenting symptom.  Its onset, however, is highly variable and may begin in infancy but almost always before the third decade of life.  The majority (77%) of patients are legally blind within a decade of onset.  The visual field may show paracentral scotomas and peripheral constriction.  Both VEPs and ERGs can be abnormal.  Diabetic retinopathy is uncommon and usually mild.

Two sibs with confirmed WFS1 have been reported with microspherophakia, congenital cataracts, and glaucoma in addition to optic atrophy .

Systemic Features: 

The clinical features of this disorder are many and highly variable.  Sensorineural hearing loss, diabetes insipidus, anemia, seizures, vasopressin deficiency, ataxia, and autonomic neuropathy are usually present. Respiratory failure secondary to brain stem atrophy may have fatal consequences by the age of 30 years.  A variety of mental disturbances including mental retardation, dementia, depression, and behavioral disorders have been reported.  The diabetes mellitus is insulin dependent with childhood onset.  Dilated ureters and neurogenic bladder are frequently seen, especially in older patients..

Genetics

Wolfram syndrome 1 is an autosomal recessive disorder that can be caused by mutations in the WFS1 gene (4p16.1) encoding wolframin, a small protein important to maintenance of the endoplasmic reticulum.  However, a minority of individuals also have deletion mutations in mitochondrial DNA (598500).  Some evidence suggests that point mutations at 4p16.1 predispose deletions in mtDNA, and, if so, this recessive disorder may owe its appearance to combined mutations in both nuclear and mitochondrial DNA.  In addition, rare families with the Wolfram syndrome phenotype and mutations in the WFS1 gene show transmission patterns consistent with autosomal dominant inheritance.

Wolfram syndrome 2 (WFS2) (604928) results from mutations in CISD2 at 4q22-q24.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment is available for Wolfram syndrome but the administration of thiamin can correct the anemia.  Low vision aids may be helpful in early stages of disease.

References
Article Title: 

Adrenoleukodystrophy, X-Linked

Clinical Characteristics
Ocular Features: 

Virtually all patients have visual symptoms.  Loss of acuity, hemianopia, visual agnosia, optic atrophy, and strabismus are the most common features.   Neuropathy may cause a decrease in corneal sensation.  Gaze abnormalities due to ocular apraxia are sometimes seen.  Ocular symptoms often occur after the systemic abnormalities are noted.  However, there is considerable heterogeneity in age of onset and progression of symptoms.

Histopathology of ocular structures reveals characteristic inclusions in retinal neurons, optic nerve macrophages, and the loss of ganglion cells with thinning of the nerve fiber layer of the retina. 

Systemic Features: 

This is a peroxisomal disorder of very-long-chain fatty acid (VLCF) metabolism that leads to progressive neurological and adrenal dysfunction from accumulation of VLCFAs in the nervous system, adrenal glands, and testes.  The age of onset and clinical course are highly variable and there may be several forms.  The childhood form begins between the ages of 4 and 8 years but in other patients with the adult form, symptoms may not appear until the third decade of life.  A viral illness may precipitate the onset.   Symptoms of both central and peripheral neurologic disease are often present with cognitive problems, ataxia, spasticity, aphasia, and loss of fine motor control.  Hearing loss is seen in some patients.  Younger patients tend to have more behavioral problems while older individuals may develop dementia.

Adrenal insufficiency leads to skin hyperpigmentation, weakness, loss of muscle mass and eventually coma.  Impotence in males is common. 

Genetics

This is an X-linked disorder secondary to mutations in the ABCD1 gene (Xp28).  The result is a deficiency in the cellular transporter known as adrenoleukodystrophy protein that is active in perioxosomes.

Although this X-linked disorder is primarily manifest in males, between 20 and 50% of female carriers have at least some symptoms, usually with a later onset than seen in males.

There are also rare cases with an apparent autosomal recessive pattern of inheritance (NALD) (202370) having an earlier onset and more aggressive course. 

Pedigree: 
X-linked recessive, carrier mother
X-linked recessive, father affected
Treatment
Treatment Options: 

Treatment of adrenal insufficiency is important and can be lifesaving.  Low vision aids, physical therapy and special education may be helpful.  Some young patients with early disease have benefitted from bone marrow transplantation.  "Lorenzo's Oil" (a mixture of oleic acid and erucic acid) has been reported to reduce or delay symptoms in some boys.

Recent reports suggest new treatment modalities may hold promise.  Infusion of autologous CD34+ cells transduced with the Lentin-D lentiviral vector reduced major symptoms in 15 of 17 boys within 29 months after treatment.  Likewise, intrathecal baclofen treatment in two boys with rapidly advancing cerebral manifestations provided symptomatic and palliative improvement.

 

References
Article Title: 

Hematopoietic Stem-Cell Gene Therapy for Cerebral Adrenoleukodystrophy

Eichler F, Duncan C, Musolino PL, Orchard PJ, De Oliveira S, Thrasher AJ, Armant M, Dansereau C, Lund TC, Miller WP, Raymond GV, Sankar R, Shah AJ, Sevin C, Gaspar HB, Gissen P, Amartino H, Bratkovic D, Smith NJC, Paker AM, Shamir E, O'Meara T, Davidson D, Aubourg P, Williams DA. Hematopoietic Stem-Cell Gene Therapy for Cerebral Adrenoleukodystrophy. N Engl J Med. 2017 Oct 4. doi: 10.1056/NEJMoa1700554. [Epub ahead of print].

PubMed ID: 
28976817

X-linked adrenoleukodystrophy

Moser HW, Mahmood A, Raymond GV. X-linked adrenoleukodystrophy. Nat Clin Pract Neurol. 2007 Mar;3(3):140-51. Review.

PubMed ID: 
17342190

Sandhoff Disease

Clinical Characteristics
Ocular Features: 

Retinal ganglion cells are rendered dysfunctional from the toxic accumulation of intra-lysosomal GM2 ganglioside molecules causing early visual symptoms.  These cells in high density around the fovea centralis create a grayish-white appearance.  Since ganglion cells are absent in the foveolar region, this area retains the normal reddish appearance, producing the cherry-red spot.  Axonal decay and loss of the ganglion cells leads to optic atrophy and blindness. 

Systemic Features: 

Sandhoff disease may be clinically indistinguishable from Tay-Sachs disease even though the same enzyme is defective (albeit in separate subunits A and B that together comprise the functional enzymes).  The presence of hepatosplenomegaly in Sandoff disease may be distinguishing. The infantile form of this lysosomal storage disease seems to be the most severe.  Infants appear to be normal until about 3-6 months of age when neurological development slows and muscles become weak.  Seizures, loss of interest, and progressive paralysis begin after this together with loss of vision and hearing.  An exaggerated startle response is considered an early and helpful sign in the diagnosis.  Among infants with early onset disease, death usually occurs by 3 or 4 years of age.   

Ataxia with spinocerebellar degeneration, motor neuron disease, dementia, and progressive dystonia are more common in individuals with later onset of neurodegeneration.  The juvenile and adult-onset forms of the disease also progress more slowly.  

Genetics

Sandhoff disease results from mutations in the beta subunit of the hexosaminidase A and B enzymes.  It is an autosomal recessive disorder caused by mutations in HEXB (5q13). 

Tay-Sachs disease (272800) can be clinically indistinguishable from Sandoff disease and they are allelic disorders.  However, the mutation in Tay-Sachs (272800) is in HEXA resulting in dysfunction of the alpha subunit of hexosaminidase A enzyme. 

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No specific treatment is available beyond general support with proper nutrition and maintainence of airways.  Anticonvulsants may be helpful in some stages.  Gene therapy in fibroblast cultures has achieved some restoration of  hexosaminidase A activity in Tay-Sachs disease and may have potential in Sandhoff disease as well. 

References
Article Title: 

Neuropathy, Ataxia, and Retinitis Pigmentosa

Clinical Characteristics
Ocular Features: 

Night blindness and visual field restriction are early symptoms usually in the second decade of life.  The retina may first show a salt-and-pepper pigmentary pattern which later resembles the classic bone-spicule pattern of retinitis pigmentosa with vascular attenuation.  The optic nerve becomes pale and eventually marked optic atrophy develops.  Severe vision loss is evident in young adults and some patients become blind. 

Systemic Features: 

The onset of systemic symptoms such as unsteadiness occurs some time in the second decade of life.  Irritability, delayed development, and psychomotor retardation may be evident in children whereas older individuals can have frank dementia.  The MRI may reveal cerebral and cerebellar atrophy.  Seizures may have their onset by the third decade.  Numbness, tingling and pain in the extremities are common.  EMG and nerve conduction studies can demonstrate a peripheral neuropathy.  Neurogenic muscle weakness can be marked and muscle biopsy may show partial denervation. Some patients have hearing loss.  A few patients have cardiac conduction defects. 

Genetics

This is a mitochondrial disorder with pedigrees showing maternal transmission.  The mutation (8993T-G) occurs in a subunit of mitochondrial H(+)-ATPase or MTATP6.  The amount of heteroplasmy is variable and likely responsible for the clinical heterogeneity in this disorder.  Individuals with more than 90% mutated chromosomes are considered to have a subtype of Leigh syndrome (MILS) with earlier onset (3-12 months of age).  NARP patients usually have 70-80% or less of mutated mitochondria.  The amount of heteroplasmy may vary among tissues. 

Treatment
Treatment Options: 

No treatment is available for this disease but low vision aids can be helpful in early stages of disease.  Recently it has been demonstrated that alpha-ketoglutarate/aspartate application to fibroblast cell cultures can provide some protection from cell death in NARP suggesting a potential therapeutic option. 

References
Article Title: 

Retinopathy of NARP syndrome

Kerrison JB, Biousse V, Newman NJ. Retinopathy of NARP syndrome. Arch Ophthalmol. 2000 Feb;118(2):298-9.

PubMed ID: 
10676807

Neuronal Ceroid Lipofuscinoses

Clinical Characteristics
Ocular Features: 

At least 13 genotypically distinct forms of neuronal ceroid lipofuscinosis have been described.  The ocular features are highly similar in all forms with blindness the end result in all types (although not all cases with an adult onset suffer vision loss).  The onset of visual signs and symptoms is highly variable.  Optic atrophy is the most common finding which may occur as early as two years of age in the infantile form.  Night blindness is a symptom in those with a later onset but panretinal degeneration with unrecordable ERGs eventually occurs.  Pigmentary changes throughout the retina are often seen and sometimes occur in a bull’s-eye pattern.  Retinal blood vessels may be attenuated and lens opacities of various types are common. 

Systemic Features: 

The neuronal ceroid lipofuscinosis are a group of inherited neurodegenerative lysosomal-storage disorders characterized by the intracellular accumulation of autofluorescent lipopigment causing damage predominantly in the central nervous system.  The result is a progressive encephalopathy with cognitive and motor decline, eventual blindness, and seizures with early death.  While early descriptions distinguished several types based primarily on age of onset, genotyping has now identified responsible mutations in at least 10 genes and time of onset is no longer considered a reliable indicator of the NCL type. 

Genetics

The NCLs are usually inherited in autosomal recessive patterns with the exception of some adult onset cases in which an autosomal dominant pattern is sometimes seen.

The various forms of NCL are often divided according to ages of onset but overlap is common.  Thus the congenital form (CLN10; 610127), caused by a mutation in the CTSD gene at 11p15.5, can have an onset of symptoms at or around birth but also is responsible for an adult form (Vida infra).  The CLN1 infantile form (256730), caused by a mutation in the PPT1 gene at 1p32, has an onset between 6 and 24 months  There are several mutations causing late infantile disease (CLN2, 204500) involving the TPP1 gene (11p15.5) leading to symptoms between 2-4 years, the CLN5 gene (256731) at 13q21.1-q32 with onset between 4 and 7 years, the CLN6 gene (601780) at 15q21-q23 showing symptoms between 18 months and 8 years, and the CLN8 gene (610003) at 8p23 with symptoms beginning between 3 and 7 years.  Another early juvenile form (CLN7; 610951) is caused by mutations in MFSD8 (4q228.1-q28.2).

A juvenile form (sometimes called Batten disease or Spielmeyer-Vogt with onset between 4 and 10 years results from mutations in CLN3 (204200) as well as in TPP1, PPT1, and CLN9 (609055).  An adult form known as ANCL or Kuf’s disease results from mutations in CTSD, PPT, CLN3, CLN5, and CLN4 (204300) and has its onset generally between the ages of 15 and 50 years. 

Homozygous mutations in the ATP13A2 gene (1p36.13), known to cause Kufor-Rakeb type parkinsonism (606693), have also been found in NCL.

Pedigree: 
Autosomal dominant
Autosomal recessive
Treatment
Treatment Options: 

Treatment is primarily symptomatic for sleep disorders, seizures, psychoses, malnutrition, dystonia and spasticity.  However, there is recent progress in the application of enzyme-replacement therapies in the soluble lysosomal forms of CNL.  Gene therapies and the use of stem cells also hold promise. 

References
Article Title: 

Niemann-Pick Disease, Type C2

Clinical Characteristics
Ocular Features: 

The primary ocular feature of type C2 Niemann-Pick disease is supranuclear gaze palsy.  A cherry red spot is rarely seen. 

Systemic Features: 

Neurodegeneration is the outstanding clinical manifestation and often the cause of death.  The onset usually occurs in infancy and the course is rapid with death often in the first year of life.  The clinical disease is similar to that of the more common type C1 (257220) although there is considerable clinical heterogeneity in all types of NPC.  Pulmonary involvement can be a prominent feature of C2 disease.  Other neurologic symptoms include ataxia, facial dyskinesis, bradykinesia, expressive aphasia, dysarthria and cognitive decline.  Visceromegaly seems to be less common than in type C1 (257220).  Cholesterol esterification is impaired with accumulation in intracellular organelles. 

Genetics

Like other types of NPC disease, this disorder follows an autosomal recessive pattern of inheritance.  It results from mutations in the NPC2 gene (14q24.3).  These mutations are far less common than those in the NPC1 (257220)gene.  

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Treatment is available for symptoms such as seizures and dystonia.  Good pulmonary hygiene is important and precautions should be taken to prevent aspiration. 

References
Article Title: 

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