muscle wasting

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: 

Spastic Ataxia 6, Charlevoix-Saguenay Type

Clinical Characteristics
Ocular Features: 

Patches of myelinated axons from retinal neurons in the retina are not unusual in the general population but are especially prominent among families in Canada with SPAX6.  These typically appear as striated white or yellowish-white patches with 'fuzzy' borders in the nerve fiber layer of the retina and radiate from the disc.   These findings are usually of no functional significance but if sufficiently large and dense can be demonstrated on perimetry as small scotomas.   OCT studies in two Belgian families have revealed increased thickness of the peri-papillary retinal nerve fiber layer in both patients and carriers without clinical evidence of myelination.  In addition the retinal nerve fiber layer has been described as 'hypertrophied' outside the areas of myelination.   Horizontal gaze nystagmus and deficits in conjugate pursuit movements are often present.   

Systemic Features: 

This neurodegenerative disorder begins in early childhood (12-18 months) with signs of cerebellar ataxia, pyramidal signs, and peripheral neuropathy.  Slightly older children develop a mixed-sensorimotor peripheral neuropathy. Dysarthria, limb spasticity, distal muscle wasting, and mitral valve prolapse are often present.  Knee reflexes are exaggerated while ankle reflexes are often absent.  Extensor plantar responses are usually present.  The EMG can show signs of denervation with slowed conduction while brain neuroimaging demonstrates regional atrophy in the cerebellum, especially the superior vermis.  Most patients eventually become wheelchair-bound.  However, cognitive and daily living skills are preserved into adulthood.  Most patients live into the sixth decade.

Genetics

Homozygous or compound heterozygous mutations in the SACS gene (13q12.12) are responsible for this autosomal recessive disorder.

The largest number of cases is found in the Charlevoix-Saguenay region of Quebec, Canada among the descendents of a founder but families have also been found in Asia and Europe.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment for the general disease is available but specific therapies for some functions such as urinary urgency are available.  Physical and speech therapy as well as special education assistance can be helpful for adaptation.

References
Article Title: 

Location score and haplotype analyses of the locus for autosomal recessive spastic ataxia of Charlevoix-Saguenay, in chromosome region 13q11

Richter A, Rioux JD, Bouchard JP, Mercier J, Mathieu J, Ge B, Poirier J, Julien D, Gyapay G, Weissenbach J, Hudson TJ, Melan?sson SB, Morgan K. Location score and haplotype analyses of the locus for autosomal recessive spastic ataxia of Charlevoix-Saguenay, in chromosome region 13q11. Am J Hum Genet. 1999 Mar;64(3):768-75. Erratum in: Am J Hum Genet 1999 Apr;64(4):1257.

PubMed ID: 
10053011

Cataracts, Congenital, and Hypomyelinating Leukodystrophy

Clinical Characteristics
Ocular Features: 

Bilateral cataracts may be present at birth or later in the first decade of life.  The ERG and flash VEPs are normal.

Systemic Features: 

Psychomotor development is initially normal but signs of delay are usually present during the first year of life.  Patients may be able to walk but only with support.  Pyramidal and cerebellar dysfunction, muscle weakness and wasting, dysarthria, truncal hypotonia, intention tremor, and spasticity are evident during the first decade.  Some have seizures.  Cognitive impairment ranges from mild to moderate.  Most patients become wheelchair-bound late in the first decade of life and some do not survive beyond childhood.

Hypomyelination and mild axonal loss may be seen in peripheral nerve biopsies while neuroimaging shows evidence of diffuse and progressive cerebral white matter atrophy.

Genetics

This is an autosomal recessive disorder caused by homozygous mutations in FAM126A (7p15.3) leading to a deficiency of the neuronal protein hyccin.  The result is deficient myelination in both central and peripheral nervous systems.  No symptoms are evident in heterozygotes.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

The cataracts may be surgically removed.  There is no known treatment for the progressive neurologic deterioration but physical therapy and special education may be helpful.

References
Article Title: 

Novel FAM126A mutations in Hypomyelination and Congenital Cataract disease

Traverso M, Assereto S, Gazzerro E, Savasta S, Abdalla EM, Rossi A, Baldassari S, Fruscione F, Ruffinazzi G, Fassad MR, El Beheiry A, Minetti C, Zara F, Biancheri R. Novel FAM126A mutations in Hypomyelination and Congenital Cataract disease. Biochem Biophys Res Commun. 2013 Aug 30. [Epub ahead of print] PubMed PMID: 23998934.

PubMed ID: 
23998934

Phenotypic characterization of hypomyelination and congenital cataract

Biancheri R, Zara F, Bruno C, Rossi A, Bordo L, Gazzerro E, Sotgia F, Pedemonte M, Scapolan S, Bado M, Uziel G, Bugiani M, Lamba LD, Costa V, Schenone A, Rozemuller AJ, Tortori-Donati P, Lisanti MP, van der Knaap MS, Minetti C. Phenotypic characterization of hypomyelination and congenital cataract. Ann Neurol. 2007 Aug;62(2):121-7.

PubMed ID: 
17683097

Oculopharyngeal Muscular Dystrophy

Clinical Characteristics
Ocular Features: 

Progressive ptosis is the cardinal ocular feature of this syndrome (present in at least 88% of patients).  External ophthalmoparesis of some degree is often present with weakness of upgaze most common.

Systemic Features: 

This is a late onset form of progressive muscular dystrophy with onset of symptoms during midlife (mean age of onset ~48 years).  Evidence of pharyngeal muscle weakness often occurs concomitantly with the ocular signs (43%).  Ptosis occurs first in 43% and dysphagia first in 14%.    Dysarthria and dysphagia are often associated with facial muscle weakness.  Swallowing times for ice cold water and dry food is usually prolonged.  Evidence of weakness and wasting of neck and limb muscles is usually noted later.  Life expectancy is normal in contrast to some other forms of muscular dystrophy.  Some patients have significant gait problems and generalized disability as a result of muscle weakness.

Microscopic studies of muscle biopsies usually show evidence of myopathy with abnormal fibers and accumulations of sarcoplasmic matter.  Intranuclear inclusions consisting of tubular filaments and mitochondrial abnormalities have also been described.  Serum CK can be significantly elevated in severe cases.  

Genetics

This is an autosomal dominant disorder resulting from mutations in the PABPN1 gene located at 14q11.2-q13. Several patients with homozygous and compound heterozygous mutations have also been reported.  The PABPN1 gene product is normally a facilitator of polyadenylation of mRNA molecules and may also be active in regulating mRNA production.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

Blepharoplasty may be helpful in cases with severe ptosis.  Cricopharyngeal myotomy for dysphagia and recurrent pneumonia can alleviate symptoms in severe cases although recurrence has been noted after many years.

References
Article Title: 

Myotonic Dystrophy 2

Clinical Characteristics
Ocular Features: 

Polychromatic lens opacities and posterior subcapsular sclerosis are found in 15-30% of patients. 

Ptosis, ophthalmoplegia and strabismus are not features of DM2.As many as 25% of patients with DM have a pigmentary retinopathy, usually in a butterfly pattern.

Systemic Features: 

Symptoms of myotonia usually appear in the third and fourth decades of life while evidence of limb girdle muscle weakness usually appears much later.  There is no infancy or childhood form of the disease and developmental delays do not occur.   In some patients the proximal muscles seem to be more affected than distal muscles and such cases are sometimes referred to as PROMM disease.  In these patients the neck and finger flexors may be the first to be affected.  However, there is considerable clinical variability.  Facial weakness is minimal.  Eventually both proximal and distal muscles weaken.  Myalgia of a burning, tearing nature can be debilitating.  Cardiac arrhythmias occur in a minority of patients.  Frontal balding is characteristic.  The long-term prognosis is better than in patients with myotonic dystrophy 1 (160900), and some but not all reports suggest fewer individuals experience age-related cognitive decline.  Insulin insensitivity and testicular failure occur in approximately half of patients.

PROMM disease and DM2 are now generally accepted as the same disease and the latter designation is preferred.

Genetics

Like classic myotonic dystrophy 1 (160900), this disorder also results from an abnormal number of repeats (in this case of CCTG).  Up to 30 tetranucleotide repeats in CNBP (3q21.3) is normal but patients with myotonic dystrophy 2 may have 11,000 or more and the number increases with age.  The repeat length may diminish with generational transmission.  Unlike DM 1, the repeat number does not seem to correlate with disease severity.  Both DM1 and DM2 are inherited in an autosomal dominant pattern.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

There is no treatment for the muscle disease but many patients require analgesic medication for muscle pain.  Visually significant cataracts should be removed.  Some patients require supportive care.

References
Article Title: 

Myotonic Dystrophy 1

Clinical Characteristics
Ocular Features: 

Posterior subcapsular cataracts may be seen at any age, often with striking iridescent opacities in the overlying cortex as well.  These polychromatic lens changes can be diagnostic but are present in only 50% of young adults with myotonic dystrophy.  When present, they are almost always bilateral.  Proximal muscle involvement leads to ptosis, strabismus, weakness of the orbicularis oculi, and sometimes ophthalmoplegia.  Such muscle weakness may lead to exposure keratitis. 

As many as 25% of patients with DM have a pigmentary retinopathy, usually in a butterfly pattern.

A low IOP and even hypotony is sometimes seen.  The mean IOP in a series of 51 patients has been reported as 10.9 compared with 15.4 in controls.  Using ultrasound biomicroscopy, ciliary body detachments were found in at least one quadrant of all eyes.

Systemic Features: 

In the congenital form, hypotonia, generalized weakness, mental retardation and respiratory insufficiency are often present.  There is a great deal of clinical heterogeneity among patients.  Those with mild disease may have only cataracts and mild myotonia with a normal life expectancy.  Those with more severe disease (classical myotonic dystrophy) have these signs plus marked muscle weakness and wasting.  Cardiac conduction defects with secondary arryhthmias are a significant cause of mortality. Such patients tend to become disabled in adulthood.  Symptoms become evident in the second decade or later.  Deep muscle pain is common and can be severe.  Distal muscle weakness usually begins before facial muscle weakness is apparent.  Myotonia often involves the tongue while proximal muscle weakness can cause dysphagia and dysarthria.  Such patients may also suffer respiratory distress. Reproductive fitness is reduced in males who can have gonadal atrophy.  Frontal balding is common.  Some age-related cognitive decline occurs.

Over 60% of patients have a hearing impairment and more than half of these have auditory brainstem response abnormalities.  Vestibular hypesthesia is present in 37.5%.

Genetics

Myotonic dystrophy 1 is an autosomal dominant disorder caused by a trinucleotide (CTG) repeat expansion in a region of the DMPK gene (19q13.2-q13.3).  The number of repeats varies widely and is roughly correlated with severity of disease.  Infants with congenital myotonia usually have the highest number of repeats and have the most severe cognitive deficits.  The number can expand during gametogenesis each generation (resulting in the phenomenon of anticipation) and females generally transmit larger numbers.  Most infants with congenital myotonia are offspring of affected mothers.  Reduced fetal movement and hydramnios are often noted during such pregnancies.

Affected males have few offspring secondary to gonadal atrophy.  Affected heterozygous females, however, do not have the expected ratio of affected offspring because of the dynamic nature of the number of repeats.  The risk of an affected offspring for a nulliparous afflicted female is only 3-9% and she has a 20-40% risk of recurrence after the birth of an affected child.

In a study of sibships with myotonic dystrophy, 58% of offspring were affected when the transmitting parent was male and 63% when the transmitting parent was female.

At least some of the variable transmission risks and clinical heterogeneity may be explained by somatic instability of the CTG repeat numbers.  The degree of instability, moreover, may also be heritable.  Age of onset, for example, is modified by the level of somatic instability.  Further, patients in whom the repeat expands more rapidly develop symptoms earlier. 

A similar disorder, myotonic dystrophy 2 (602668), is caused by a tetranucleotide repeat expansion in the CNBP gene.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

A variety of pharmaceutical agents have been tried for pain management without consistent results.  No treatment improves the muscle weakness.  Cholesterol lowering drugs such as statins should be avoided.  Physical therapy may be helpful.

Cardiac conduction and structural defects are a significant threat even in asymtomatic patients and require constant monitoring for the development of arrythmias.

References
Article Title: 

Inner ear dysfunction in myotonic dystrophy type 1

Balatsouras DG, Felekis D, Panas M, Xenellis J, Koutsis G, Kladi A, Korres SG. Inner ear dysfunction in myotonic dystrophy type 1. Acta Neurol Scand. 2012 Nov 5. doi: 10.1111/ane.12020. [Epub ahead of print].

PubMed ID: 
23121018

Somatic instability of the expanded CTG triplet repeat in myotonic dystrophy type 1 is a heritable quantitative trait and modifier of disease severity

les F, Couto JM, Higham CF, Hogg G, Cuenca P, Braida C, Wilson RH, Adam B, Del Valle G, Brian R, Sittenfeld M, Ashizawa T, Wilcox A, Wilcox DE, Monckton DG. Somatic instability of the expanded CTG triplet repeat in myotonic dystrophy type 1 is a heritable quantitative trait and modifier of disease severity. Hum Mol Genet. 2012 May 16. [Epub ahead of print].

PubMed ID: 
22595968

Incidence and predictors of sudden death, major conduction defects and sustained ventricular tachyarrhythmias in 1388 patients with myotonic dystrophy type 1

Wahbi K, Babuty D, Probst V, Wissocque L, Labombarda F, Porcher R, Becane HM, Lazarus A, Behin A, Laforet P, Stojkovic T, Clementy N, Dussauge AP, Gourraud JB, Pereon Y, Lacour A, Chapon F, Milliez P, Klug D, Eymard B, Duboc D. Incidence and predictors of sudden death, major conduction defects and sustained ventricular tachyarrhythmias in 1388 patients with myotonic dystrophy type 1. Eur Heart J. 2016 Dec 9. pii: ehw569. [Epub ahead of print] PubMed.

PubMed ID: 
27941019
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