distal muscle weakness

Ataxia with Oculomotor Apraxia 3

Clinical Characteristics
Ocular Features: 

Ocular movement abnormalities are noted at the same time as other peripheral motor difficulties.  Slow saccadic eye movements, and head-eye lag are evident.  Pursuit movements are normal.

Systemic Features: 

Onset of gait instability occurs in the second decade of life with dysmetria and frequent falls. The eye movement abnormalities, dysarthria, and axial dysmetria with distal muscle atrophy and weakness are present at the same time.  Distal sensory deficits with lack of sensory nerve action potentials are also present in the lower limbs.  The upper limbs are involved somewhat later but with less pronounced movement impairment.  Hyporeflexia or areflexia is common.  The disorder is progressive with loss of independent mobility by the third decade.

Brain and spinal cord MRI imaging reveals cerebellar atrophy of the folia and vermis.  Persistently elevated alpha-fetoprotein levels have been found but no hypoalbuminemia.

Genetics

Homozygous missense mutations in the PIK3R5 gene (17p12-p13) have been associated with this clinical picture in one family of 4 affected sibs born of consanguineous parents.

See also Ataxia with Oculomotor Apraxia 1 (208920) with hypoalbuminemia, Ataxia with Oculomotor Apraxia 2 (606002) (also known as Spinocerebellar Ataxia, Autosomal Recessive 1 or SCAR1), and Ataxia with Oculomotor Apraxia 4 (616267).

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment has been reported.

References
Article Title: 

Mitochondrial DNA Depletion Syndrome 1

Clinical Characteristics
Ocular Features: 

Progressive external ophthalmoplegia has an adult onset, usually in the late second or early third decade of life.  Ptosis is commonly present as well.

Systemic Features: 

This condition has been called a mitochondrial neurogastrointestinal encephalopathy (MNGIE).  Gastrointestinal problems are among the most disabling with poor absorption of foodstuffs leading to weight loss, marked cachexia, and chronic malnutrition.  Added to this are gastroparesis, constipation, vomiting, and intermittent diarrhea with abdominal pain.  Many individuals develop diverticulosis and diverticulitis that may lead to intestinal perforations.  The combined intestinal dysfunctions can lead to signs of intestinal pseudoobstruction.

Many patients have a progressive sensorineural hearing loss.  Leukoencephalopathy, sensorimotor peripheral neuropathy, and sometimes mild proximal limb weakness may be present.

Genetics

Homozygous and compound heterozygous mutations in the TYMP gene (22q13.33) are responsible for this autosomal recessive disorder.  This nuclear gene is active in the maintainence of mitochondrial DNA.  When the gene is dysfunctional, the mitochondria can be depleted to a variable extent and they may contain multiple deletions and point mutations.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

There is no effective treatment for the overall condition.  Nutritionists can provide important advice on diet to maintain good nutrition.  Regular monitoring by gastroenterologists is important.  Perforations of the bowels require prompt surgical repair.  

References
Article Title: 

Mitochondrial neurogastrointestinal encephalomyopathy: an autosomal recessive disorder due to thymidine phosphorylase mutations

Nishino I, Spinazzola A, Papadimitriou A, Hammans S, Steiner I, Hahn CD, Connolly AM, Verloes A, Guimaraes J, Maillard I, Hamano H, Donati MA, Semrad CE, Russell JA, Andreu AL, Hadjigeorgiou GM, Vu TH, Tadesse S, Nygaard TG, Nonaka I, Hirano I, Bonilla E, Rowland LP, DiMauro S, Hirano M. Mitochondrial neurogastrointestinal encephalomyopathy: an autosomal recessive disorder due to thymidine phosphorylase mutations. Ann Neurol. 2000 Jun;47(6):792-800.

PubMed ID: 
10852545
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