muscle weakness

Spastic Paraplegia 5A

Clinical Characteristics
Ocular Features: 

Gaze-evoked nystagmus and saccadic pursuit movements are present in about 10% of patients.  Optic atrophy was reported in one individual.  Rare patients have been reported to have cataracts.  

Systemic Features: 

This is a progressive disorder of neurological deterioration.  Age of onset (mean 16.4 years) and rate of neurological dysfunction are highly variable.  Gait difficulties are the most common presenting signs.  Some gait ataxia is usually present.  The lower limbs are more severely affected by spasticity and weakness and walking is often delayed with difficulty running and clumsiness in childhood.  Some patients (38%) are wheelchair-bound after disease duration of more than 33 years.  Dysphagia and dysarthria are uncommon. 

Some sensory impairments such as impaired vibratory sense, decreased proprioception, and absent touch sensation in the lower extremities are frequently present.  Urge incontinence of bladder and rectum is sometimes a feature.

Genetics

Bialllelic mutations in the CYP7B1 gene (8q12.3) have been identified in this disorder resulting in a marked accumulation of neurotoxic oxysterols in plasma and CSF.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No effective treatment for the general disorder has been reported.

References
Article Title: 

Hereditary spastic paraplegia type 5: natural history, biomarkers and a randomized controlled trial

Schols L, Rattay TW, Martus P, Meisner C, Baets J, Fischer I, Jagle C, Fraidakis MJ, Martinuzzi A, Saute JA, Scarlato M, Antenora A, Stendel C, Hoflinger P, Lourenco CM, Abreu L, Smets K, Paucar M, Deconinck T, Bis DM, Wiethoff S, Bauer P, Arnoldi A, Marques W, Jardim LB, Hauser S, Criscuolo C, Filla A, Zuchner S, Bassi MT, Klopstock T, De Jonghe P, Bjorkhem I, Schule R. Hereditary spastic paraplegia type 5: natural history, biomarkers and a randomized controlled trial. Brain. 2017 Dec 1;140(12):3112-3127.

PubMed ID: 
29126212

CYP7B1 mutations in pure and complex forms of hereditary spastic paraplegia type 5

Goizet C, Boukhris A, Durr A, Beetz C, Truchetto J, Tesson C, Tsaousidou M, Forlani S, Guyant-Marechal L, Fontaine B, Guimaraes J, Isidor B, Chazouilleres O, Wendum D, Grid D, Chevy F, Chinnery PF, Coutinho P, Azulay JP, Feki I, Mochel F, Wolf C, Mhiri C, Crosby A, Brice A, Stevanin G. CYP7B1 mutations in pure and complex forms of hereditary spastic paraplegia type 5. Brain. 2009 Jun;132(Pt 6):1589-600.

PubMed ID: 
19439420

Myopathy, Mitochondrial Anomalies, and Ataxia

Clinical Characteristics
Ocular Features: 

Ocular findings are variable.  One of three individuals with compound heterozygous mutations had a pigmentary retinopathy with pallor of the optic nerve but no visual abnormalities.  Her sister had only optic nerve pallor.  The eyes are described as "small" and "close-set".

No ocular findings were reported for the family with autosomal dominant inheritance.

Systemic Features: 

Ataxia, short stature, and gait difficulties from an early age are consistent findings.  Some patients are never able to walk.  Motor development is generally delayed.  Truncal and limb ataxia is a feature.  Some degree of intellectual disability is generally present and speech is often delayed.  

The face is long with a myopathic appearance.  Both micrognathia and a prominent jaw may be seen.  The palate is highly arched.  Patients are described as hypotonic and there is generalized muscle weakness both proximal and distal.  Distal sensory impairment has been described in the family with presumed dominant inheritance and there may be psychiatric symptoms of anxiety, depression, and schizophrenia.  Dysmetria with dysdiadochokinesis is often present and a fine intention tremor has been observed.

Mitochondria in fibroblasts exhibit abnormal dynamics and occur in a fragmented network.  Muscle biopsies reveal changes consistent with myopathy.  Serum creatine kinase may be elevated.

Genetics

Compound heterozygous mutations in the MSTO1 gene (1q22) have been found in two families with 3 affected individuals suggesting autosomal recessive inheritance.  In a third family, heterozygous mutations in the same gene were found in a mother and 3 of her adult children, consistent with autosomal dominant transmission.

Pedigree: 
Autosomal dominant
Autosomal recessive
Treatment
Treatment Options: 

No treatment has been reported.

References
Article Title: 

Birk-Landau-Perez Syndrome

Clinical Characteristics
Ocular Features: 

Patients have oculomotor apraxia, saccadic pursuits, lack of fixation, and ptosis.  No pigmentary changes were seen in the fundi but the optic nerves have not been described.

Systemic Features: 

This is a progressive disorder in which psychomotor regression and loss of speech develop by 1 to 2 years of age, often appearing as the first sign of abnormalities.  Cognitive impairment can progress to profound intellectual disability.  Older patients have limb and truncal ataxia and experience frequent falls.  Muscle tone in the limbs is increased and children often exhibit dyskinesia, dystonia, and axial hypotonia.  General muscle weakness is often present.  No abnormalities have been seen on brain imaging.

Some patients develop a nephropathy with renal insufficiency, hypertension, and hyperechogenic kidneys though deterioration of the renal disease is slow.  Renal biopsy in one patient revealed tubulointerstitial nephritis but no individuals have reached end-stage renal failure.

Genetics

Homozygous mutations in the SLC30A9 gene (4p13) are responsible for this disorder.  A single multigenerational consanguineous Bedouin family of 6 affected individuals has been reported with a transmission pattern consistent with autosomal recessive inheritance.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment for the general disorder has been reported.  Electrolytes should be monitored and metabolic issues resulting from kidney malfunction may need to be addressed.

References
Article Title: 

Nemaline Myopathy 10

Clinical Characteristics
Ocular Features: 

Ophthalmoplegia has been reported in 29% of patients.

Systemic Features: 

In this form of nemaline myopathy, polyhydramnios, weak or absent fetal movements, and joint contractures may be noted during the antenatal period.  Hypotonia and generalized weakness, respiratory difficulties, feeding difficulties and evidence of bulbar weakness may be noted at birth.  Many patients die of respiratory failure in the neonatal period but some may survive into the second decade. 

Cardiac function is normal.

Genetics

This autosomal recessive disorder results from homozygous or compound heterozygous mutations in the LMOD3 gene (3p14.1).  This gene is expressed in both skeletal and cardiac muscle and its product is essential for the organization of sarcomeric thin filaments in skeletal muscle.

Mutations in at least 10 genes cause nemaline myopathy.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No general treatment is available for this condition but supportive care such as respiratory assistance and feeding supplementation may be helpful.  Physical therapy and special education may be helpful.

References
Article Title: 

Leiomodin-3 dysfunction results in thin filament disorganization and nemaline myopathy

Yuen M, Sandaradura SA, Dowling JJ, Kostyukova AS, Moroz N, Quinlan KG, Lehtokari VL, Ravenscroft G, Todd EJ, Ceyhan-Birsoy O, Gokhin DS, Maluenda J, Lek M, Nolent F, Pappas CT, Novak SM, D'Amico A, Malfatti E, Thomas BP, Gabriel SB, Gupta N, Daly MJ, Ilkovski B, Houweling PJ, Davidson AE, Swanson LC, Brownstein CA, Gupta VA, Medne L, Shannon P, Martin N, Bick DP, Flisberg A, Holmberg E, Van den Bergh P, Lapunzina P, Waddell LB, Sloboda DD, Bertini E, Chitayat D, Telfer WR, Laquerriere A, Gregorio CC, Ottenheijm CA, Bonnemann CG, Pelin K, Beggs AH, Hayashi YK, Romero NB, Laing NG, Nishino I, Wallgren-Pettersson C, Melki J, Fowler VM, MacArthur DG, North KN, Clarke NF. Leiomodin-3 dysfunction results in thin filament disorganization and nemaline myopathy. J Clin Invest. 2014 Nov;124(11):4693-708. Erratum in: J Clin Invest. 2015 Jan;125(1):456-7.

PubMed ID: 
25250574

Charcot-Marie-Tooth Disease(s)

Clinical Characteristics
Ocular Features: 

Optic atrophy is present in some patients, particularly in X-linked recessive (CMTX5; 311070), X-linked dominant (CMTX5; 302800), and autosomal recessive (CMT2A2B; 617087) disease.  Congenital and juvenile-onset open-angle glaucoma has been reported among members of 2 consanguineous families with type 4B2, or CMT4B2; (604563).  The mean age of onset was 8 years.

Systemic Features: 

Charcot-Marie-Tooth disease is a large group of clinically and genetically heterogeneous disorders characterized by progressive motor and sensory polyneuropathy.  These can be separated (with overlap) into two large groups on the basis of electrophysiologic criteria: type 1 is the demyelinating form, and type 2 the axonal form.  Patients with primarily distal motor neuropathy are sometimes considered to comprise a third type.

 Symptoms such as weakness in the extremities and digits have a variable age of onset but usually become evident in late childhood or early adulthood.  Small muscles of the hands and feet are often atrophied to some degree.  Some patients develop hearing loss of the neurosensory type.  Foot deformities such as pes cavus are common.  Nerve conduction velocity (reduction) and electromyography can be helpful diagnostically.  It may be helpful to look for characteristic changes such as loss of myelinated fibers and focal myelin sheath folding in sural nerve biopsies.  Intellectual impairment and dementia are usually not features of Charcot-Marie-Tooth disease.

Hemizygous individuals with X-linked types of CMT such as CMTX2-5 seem to be more likely to have intellectual disabilities, hearing loss, spasticity, and optic neuropathy.

Genetics

Charcot-Marie-Tooth disease can also be classified on the basis of their hereditary patterns including autosomal dominant, autosomal recessive, X-linked recessive, and X-linked dominant.  Each of these contains yet more distinct subtypes as defined by mutations in at least 40 genes.

The wide range of disease severity and the overlapping of many signs can make pedigree construction and the determination of recurrence risks and prognosis challenging.  The only recourse may be genotyping.

See Charcot-Marie-Tooth Disease with Glaucoma (604563) for a form of this disease in which glaucoma occurs early.

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

The widespread and debilitating polyneuropathy requires a multidisciplinary management approach with neurologists, physical and occupational therapists, audiologists, pain specialists, and orthopedists.  Pharmaceuticals such as gabapentin may be used for neuropathic pain.  Surgery for pes cavus and joint dysplasias can be helpful.

References
Article Title: 

Charcot-Marie-Tooth disease

Carter GT, Weiss MD, Han JJ, Chance PF, England JD. Charcot-Marie-Tooth disease. Curr Treat Options Neurol. 2008 Mar;10(2):94-102.

PubMed ID: 
18334132

Mutations in MTMR13, a new pseudophosphatase homologue of MTMR2 and Sbf1, in two families with an autosomal recessive demyelinating form of Charcot-Marie-Tooth disease associated with early-onset glaucoma

Azzedine H, Bolino A, Taieb T, Birouk N, Di Duca M, Bouhouche A, Benamou S, Mrabet A, Hammadouche T, Chkili T, Gouider R, Ravazzolo R, Brice A, Laporte J, LeGuern E. Mutations in MTMR13, a new pseudophosphatase homologue of MTMR2 and Sbf1, in two families with an autosomal recessive demyelinating form of Charcot-Marie-Tooth disease associated with early-onset glaucoma. Am J Hum Genet. 2003 May;72(5):1141-53.

PubMed ID: 
12687498

Spastic Paraplegia 46

Clinical Characteristics
Ocular Features: 

Congenital cataracts (not further described) have been reported in several individuals with this type of complicated spastic paraplegia.  Optic atrophy and nystagmus have not been reported.

Systemic Features: 

Stiffness and weakness of the lower limbs begins between 2 and 20 years of age.  This is slowly progressive although most individuals are still mobile with mild to moderate handicaps into the 4th decade.  The gait is spastic with weakness, hyperreflexia, and extensor plantar responses in the lower limbs.  The upper limbs are variably involved and movements are dysmetric.  Dysarthria and bladder dysfunction are often present.  Cerebellar ataxia is common and some patients first present with this as a prominent sign in the first and second decades.  Early cognitive development is normal but mild cognitive decline appears eventually.  Pes cavus and scoliosis may occur.

Brain imaging can show thinning of the corpus callosum, with mild cerebellar and cerebral atrophy.

Genetics

Linkage analysis identified a locus at 9p13.3 and sequencing confirmed homozygous or compound heterozygous mutations in GBA2.  The presence of parental consanguinity in some families supports autosomal recessive inheritance.

This database contains two other types of autosomal spastic paraplegia with ocular signs: spastic paraplegia 15 (270700) with a “flecked retina”, and spastic paraplegia 7 (607259) with optic atrophy and nystagmus.  Cataracts have not been reported in these two conditions.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No effective treatment is known for the neurological deficits but cataract surgery may be beneficial for visually significant cataracts.

References
Article Title: 

Mutations in GBA2 cause autosomal-recessive cerebellar ataxia with spasticity

Hammer MB, Eleuch-Fayache G, Schottlaender LV, Nehdi H, Gibbs JR, Arepalli SK, Chong SB, Hernandez DG, Sailer A, Liu G, Mistry PK, Cai H, Shrader G, Sassi C, Bouhlal Y, Houlden H, Hentati F, Amouri R, Singleton AB. Mutations in GBA2 cause autosomal-recessive cerebellar ataxia with spasticity. Am J Hum Genet. 2013 Feb 7;92(2):245-51. PubMed PMID: 23332917.

PubMed ID: 
23332917

Loss of function of glucocerebrosidase GBA2 is responsible for motor neuron defects in hereditary spastic paraplegia

Martin E, Sch?ole R, Smets K, Rastetter A, Boukhris A, Loureiro JL, Gonzalez MA, Mundwiller E, Deconinck T, Wessner M, Jornea L, Oteyza AC, Durr A, Martin JJ, Schols L, Mhiri C, Lamari F, Z?ochner S, De Jonghe P, Kabashi E, Brice A, Stevanin G. Loss of function of glucocerebrosidase GBA2 is responsible for motor neuron defects in hereditary spastic paraplegia. Am J Hum Genet. 2013 Feb 7;92(2):238-44. PubMed PMID: 23332916.

PubMed ID: 
23332916

A new locus (SPG46) maps to 9p21.2-q21.12 in a Tunisian family with a complicated autosomal recessive hereditary spastic paraplegia with mental impairment and thin corpus callosum

Boukhris A, Feki I, Elleuch N, Miladi MI, Boland-Aug?(c) A, Truchetto J, Mundwiller E, Jezequel N, Zelenika D, Mhiri C, Brice A, Stevanin G. A new locus (SPG46) maps to 9p21.2-q21.12 in a Tunisian family with a complicated autosomal recessive hereditary spastic paraplegia with mental impairment and thin corpus callosum. Neurogenetics. 2010 Oct;11(4):441-8.

PubMed ID: 
20593214

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

Danon Disease

Clinical Characteristics
Ocular Features: 

The ocular features of Danon disease are less well known than the systemic manifestations and are as yet not fully delineated likely because not all patients have visual symptoms or fundus changes.  The most commonly described fundus abnormalities are pigmentary changes variously called a peripheral pigmentary retinopathy or a pigmentary atrophy in some cases.   Changes in pigmentation may be mild in both affected males and carrier females, but are generally more severe in males.  A bulls-eye maculopathy and color vision deficiencies have been described.  Loss of visual acuity is variable and may lead to symptoms before myopathy is evident.  Vision loss is usually progressive and may be reduced to hand motions.  OCT shows thinning of the photoreceptor and RPE layers.  The full field ERG is reduced in amplitude consistent with a generalized cone-rod dystrophy.

Systemic Features: 

This disorder, originally believed to be a type of glycogen storage disease, is actually a form of autophagic vacuolar myopathy.    The characteristic vacuoles are found in muscle cytoplasm surrounded by sarcolemmal proteins and basal lamina.  The primary extraocular disease occurs in the myocardium although skeletal muscle may also be involved.  Intellectual disability is a variable and inconsistent feature.  

Cardiac rhythm abnormalities are common and include AV nodal block, atrial fibrillation, and Wolff-Parkinson-White EKG findings.  Hypertrophic cardiomyopathy (and sometimes dilated cardiomyopathy) with primary involvement of the left ventricle is common.  Symptoms typically occur in males before the age of 20 years and somewhat later in females.

Some patients have muscular weakness and exercise intolerance.  Diagnosis can be made when the characteristic vacuoles are present in a muscle biopsy but their absence does not rule out the diagnosis.

Genetics

This is an X-linked dominant disorder caused by mutations in LAMP2 (Xp24).  Females are generally less severely affected than males. Most men with Danon disease have some intellectual disability as well as skeletal myopathy but these features are found in less than half of affected women.  

Pedigree: 
X-linked dominant, father affected
X-linked dominant, mother affected
Treatment
Treatment Options: 

No known treatment is available for the ocular disease.  Transplantation can be an effective treatment for the cardiomyopathy which can be lethal even in adolescents.

References
Article Title: 

Cardiac arrhythmias in patients with Danon disease

Konrad T, Sonnenschein S, Schmidt FP, Mollnau H, Bock K, Ocete BQ, Munzel T, Theis C, Rostock T. Cardiac arrhythmias in patients with Danon disease. Europace. 2016 Oct 14. pii: euw215.

PubMed ID: 
27742774

Cone-rod dystrophy in Danon disease

Brodie S. Cone-rod dystrophy in Danon disease. Graefes Arch Clin Exp Ophthalmol. 2012 Mar 10. [Epub ahead of print].

PubMed ID: 
22407291

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

Oculopharyngodistal Myopathy

Clinical Characteristics
Ocular Features: 

Progressive ptosis, which may be asymmetric, is an early sign.  Extraocular palsy occurs as well. 

Systemic Features: 

The mean age of onset of this progressive disease is 22 years.  Pharyngeal and distal limb muscles seem to be primarily involved.  Weakness in masseter, facial, and bulbar muscles have been observed but no muscle group seems to be spared.  Atrophy of facial muscles is common and may be pronounced.  There is considerable variability in expression, particularly in the degree of limb weakness which often appears by the fifth decade.  Swallowing difficulties can be severe.  Respiratory weakness may be evident relatively early, even while patients are still ambulatory.  Loss of ambulation most commonly occurs by the third or fourth decade after the onset of first symptoms.  Serum creatine kinase levels are mildly elevated and histologic changes show chronic myopathic changes with rimmed vacuole formation.  No changes have been found in the central or peripheral nervous system. 

Genetics

The causative mutation has not been identified but mutations causing other forms of hereditary myopathy have been ruled out.  Most families are consistent with autosomal dominant inheritance but the pattern in at least one family has suggested a recessive pattern indicating genetic heterogeneity. 

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

Supportive treatment such as physical and respiratory therapies may be helpful but no specific treatment is available for the muscle disease.

References
Article Title: 

Oculopharyngodistal myopathy

Satoyoshi E, Kinoshita M. Oculopharyngodistal myopathy. Arch Neurol. 1977 Feb;34(2):89-92.

PubMed ID: 
836191

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