pes cavus

Spastic Paraplegia 11

Clinical Characteristics
Ocular Features: 

Gaze evoked nystagmus and pigmentation in the macula are components of this syndrome and adults have some degree of retinal degeneration with poor vision eventually.  Optic atrophy and ptosis have been reported but rarely.   

Systemic Features: 

his progressive condition nay have its onset in childhood or early adolescence although rarely it first appears in adulthood.  Obesity is a component in older individuals.  Loss of ambulation usually occurs within 10 years of the onset of gait difficulties.  Hyperreflexia and spasticity develop early while ataxia, urinary sphincter disturbances, extensor plantar responses, and dysarthria appear later.  Amyotrophy is frequently seen in the thenar and hypothenar muscles.  Children have learning difficulties while cognitive decline and frank mental retardation occur somewhat later.  

Peripheral nerve biopsy may reveal hypomyelination and loss of unmyelinated nerve fibers.  MRI imaging in some individuals shows a thin or absent corpus callosum and cortical atrophy. 

Genetics

Homozygous mutations in the gene SPG11 (15q21.1) encoding spatacsin are responsible for this disorder. 

See spastic paraplegia 15 (Kjellin syndrome) (270700) and spastic paraplegia 7 (607259) for other disorders with retinal degeneration, optic atrophy, and nystagmus.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

None known.

References
Article Title: 

Mutations in SPG11, encoding spatacsin, are a major cause of spastic paraplegia with thin corpus callosum

Stevanin G, Santorelli FM, Azzedine H, Coutinho P, Chomilier J, Denora PS, Martin E, Ouvrard-Hernandez AM, Tessa A, Bouslam N, Lossos A, Charles P, Loureiro JL, Elleuch N, Confavreux C, Cruz VT, Ruberg M, Leguern E, Grid D, Tazir M, Fontaine B, Filla A, Bertini E, Durr A, Brice A. Mutations in SPG11, encoding spatacsin, are a major cause of spastic paraplegia with thin corpus callosum. Nat Genet. 2007 Mar;39(3):366-72.

PubMed ID: 
17322883

Spastic Paraplegia 74

Clinical Characteristics
Ocular Features: 

Onset of visual impairment occurs at ages of 10-14 years with optic pallor evident on fundoscopy. MRI imaging reveals physical atrophy of the optic nerve.  Visual acuity ranges from 0.5 to finger counting.  Visual field defects include central scotomas and peripheral concentric constriction.

Systemic Features: 

Symptoms consisting of a spastic gait and distal sensory impairment usually appear in the first decade and are slowly progressive.  Increased deep tendon reflexes and extensor plantar responses may be present at that time but later distal leg muscle atrophy and pes cavus appear.  The ankle reflexes later disappear.  Cognitive function is normal and adults are able to lead an independent life.

Nerve conduction studies in 4 individuals showed reduced muscle action potentials and velocity while sensory conduction was normal.  Cerebellar atrophy along with an attenuated corpus callosum and cervical spinal cord atrophy was noted on MRI imaging in one of 3 studied patients.

Genetics

A homozygous splice site mutation in IBA57 (1q42) has been found to segregate with this condition in a large consanquineous Arab family.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment is known for the basic disease but physical therapy and low vision aids are likely beneficial.

References
Article Title: 

Fe S protein assembly gene IBA57 mutation causes hereditary spastic paraplegia

Lossos A, Stumpfig C, Stevanin G, Gaussen M, Zimmerman BE, Mundwiller E, Asulin M, Chamma L, Sheffer R, Misk A, Dotan S, Gomori JM, Ponger P, Brice A, Lerer I, Meiner V, Lill R. Fe/S protein assembly gene IBA57 mutation causes hereditary spastic paraplegia. Neurology. 2015 Feb 17;84(7):659-67.

PubMed ID: 
25609768

Optic Atrophy, Areflexia, Ataxia, Hearing Loss

Clinical Characteristics
Ocular Features: 

Progressive optic atrophy is a consistent feature of all reported cases.  It may have its onset during the first year or two of life but always before the age of 10 years.  Nystagmus may be seen early during acute febrile episodes but eventually becomes permanent.

Systemic Features: 

Onset of neurological symptoms usually occurs in childhood during or following an acute febrile illness which may be recurrent.  This may consist of cerebellar ataxia, hypotonia, drowsiness, dysarthria, and lethargy.  There may be partial or full recovery following the febrile illness initially but some signs remain after subsequent episodes.  Areflexia and sensorineural deafness can be additional signs and pes cavus eventually appears.

The acute febrile episodes tend to decrease in time along with the progression of neurological signs.  Plantar responses remain normal while peripheral neuropathy and seizures are not consistent features.  MRI imaging of the brain is normal.  Cognitive function usually remains normal but some children have autism features and social adjustment problems have been noted.

Genetics

This is an autosomal dominant condition (which may be considered a form of ‘ataxia-plus’) secondary to heterozygous mutations in the ATP1A3 gene (19q13.31).  The protein product is a subunit of an ATPase enzyme primarily active in neural tissue.

Other mutations in the same gene have been found in dystonia-12 and alternating hemiplegia of childhood.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

No treatment is known for this condition but physical therapy and mobility-assistive devices may be helpful.  Low vision aids may be useful as well.

References
Article Title: 

A novel recurrent mutation in ATP1A3 causes CAPOS syndrome

Demos MK, van Karnebeek CD, Ross CJ, Adam S, Shen Y, Zhan SH, Shyr C, Horvath G, Suri M, Fryer A, Jones SJ, Friedman JM; FORGE Canada Consortium. A novel recurrent mutation in ATP1A3 causes CAPOS syndrome. Orphanet J Rare Dis. 2014 Jan 28;9:15.

PubMed ID: 
24468074

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

Retinitis Pigmentosa, Hearing Loss, Ataxia, Cataract, and Polyneuropathy

Clinical Characteristics
Ocular Features: 

Cataracts and a pigmentary retinopathy occur in this condition but only in some, primarily older, patients.  The lens opacities progress and may become visually significant by the third decade.  Bone-spicule-shaped pigment clumping may be present in the midperiphery while the optic disk is often pale and the retinal vessels are attenuated. The ERG responses are consistent with a rod-cone dystrophy.

Systemic Features: 

This is a progressive neurological disorder with onset of signs and symptoms in childhood although full expression may not occur until adulthood.  Young children can have hyporeflexia, pes cavus, spasticity, and gait ataxia.  A sensorineural hearing loss may also be present in childhood but sometimes not until later.  Hyperreflexia with extensor plantar responses and Achilles tendon contractures are often present later.  The peripheral polyneuropathy is predominantly demyelinating with both sensory and motor components and is present in all adults.  Cerebellar atrophy, primarily in the vermis, can be demonstrated on MRI examination.  Mental function is usually not impaired. Some patients have dysarthria. 

This disorder has some clinical similarities to Refsum disease (266500).

Genetics

This is an autosomal recessive disorder resulting from homozygous mutations in the ABHD12 gene (20p11.21).

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Treatment is directed at symptoms.  Visually significant cataracts may require removal.  Low vision aids and physical therapy can be helpful.

References
Article Title: 

Mutations in ABHD12 cause the neurodegenerative disease PHARC: An inborn error of endocannabinoid metabolism

Fiskerstrand T, H'mida-Ben Brahim D, Johansson S, M'zahem A, Haukanes BI, Drouot N, Zimmermann J, Cole AJ, Vedeler C, Bredrup C, Assoum M, Tazir M, Klockgether T, Hamri A, Steen VM, Boman H, Bindoff LA, Koenig M, Knappskog PM. Mutations in ABHD12 cause the neurodegenerative disease PHARC: An inborn error of endocannabinoid metabolism. Am J Hum Genet. 2010 Sep 10;87(3):410-7.

PubMed ID: 
20797687

Friedreich Ataxia 1

Clinical Characteristics
Ocular Features: 

Nystagmus and optic atrophy are important ocular signs.  The visual pathway, both anterior and posterior, is consistently involved and field defects are common even though many patients are asymptomatic.  OCT usually shows a reduced nerve fiber layer secondary to loss of axons.  About half of patients have abnormal visual evoked potentials.  A few patients experience a sudden loss of central vision during the second decade of life.

Systemic Features: 

Friedreich ataxia is a progressive neurodegenerative disorder with onset before puberty.  The spinocerebellar tracts, dorsal columns, pyramidal tracts, cerebellum, medulla, and optic radiation, may all be involved.  The outstanding symptom is ataxia with impairment of gait and weakness in the limbs.  Muscle weakness, extensor plantar responses, and absent lower limb reflexes are usually present.  Dysarthria is usually notable.  Sensory signs include impairment of position and vibratory senses.  'Twitching' in limbs and digits is often noted and 'restless leg syndrome' is common.

Secondary changes include pes cavus, scoliosis, and hammer toe.  Cardiac disease is frequently present and heart failure is the most common cause of death.  Most patients have hypertrophic cardiomyopathy with characteristic EKG changes and some have subaortic stenosis as part of the hypertrophied myocardium.  Diabetes mellitus is present in 20-25%.  Some hearing loss occurs in more than 10% of individuals.

Most patients require a wheelchair within 15 years of disease onset and the mean age of death is about 36 years.

Rare patients with a later onset of FRDA retain lower limb deep tendon reflexes.

Genetics

Homozygous mutations in FXN (9p21.11) are responsible for Friedreich ataxia.  The most common DNA abnormality is a GAA trinucleotide repeat expansion in intron 1.  The number of repeats in patients is 70 to more than 1000 compared with 5-30 in normal individuals.  FXN encodes the mitochondrial protein frataxin.

About 2% of individuals have point mutations in FXN instead of trinucleotide repeats.

Some of the phenotypic variations may be explained by differences in the number of GAA repeats.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Treatment is largely directed at symptoms including speech and physical therapy and mobility assistive devices. Scoliosis may require surgical intervention.

References
Article Title: 

Visual system involvement in patients with Friedreich's ataxia

Fortuna F, Barboni P, Liguori R, Valentino ML, Savini G, Gellera C, Mariotti C, Rizzo G, Tonon C, Manners D, Lodi R, Sadun AA, Carelli V. Visual system involvement in patients with Friedreich's ataxia. Brain. 2009 Jan;132(Pt 1):116-23.

PubMed ID: 
18931386

Friedreich ataxia: an overview

Delatycki MB, Williamson R, Forrest SM. Friedreich ataxia: an overview. J Med Genet. 2000 Jan;37(1):1-8. Review.

PubMed ID: 
10633128

Multiple Endocrine Neoplasia, Type IIB

Clinical Characteristics
Ocular Features: 

Corneal nerves are medullated and appear prominent.  Neuromas of the lid margins and sometimes the conjunctiva are common features.  Thickening of the entire eyelids may be present.

Systemic Features: 

Some manifestations may be seen in early childhood.  Prominent physical features include full lips, thickened eyelids, high arched palate and a marfanoid habitus.  Medullary carcinoma of the thyroid is almost always present and can be the cause of death in relatively young individuals. Metastases are usually to the regional lymph nodes or to liver, lungs, or bone. Pheochromocytomas and megacolon secondary to gastrointestinal neuromas are commonly seen.  The esophagus sometimes lacks normal motility for the same reason.  Neuromas often lead to thickening of the lips and tongue and can also appear as pedunculated nodules on these structures.  Cafe-au-lait spots and increased pigmentation of the hands, feet, and circumoral areas are frequently present.  Many patients have dysmorphic features suggestive of Marfan syndrome including a typical habitus, pectus excavatum, scoliosis, and pes cavus. Proximal myopathy and peripheral neuropathy are sometimes seen.

Another form of multiple endocrine neoplasia, called MEN2A, differs in the absence of mucosal neuromas and the marfanoid habitus.  MEN2A patients are more likely to have parathyroid hyperplasia.

Genetics

This is an autosomal dominant disorder caused by mutations in the tyrosine kinase domain of the RET gene (10q11.2). This disorder (MEN2B) may be allelic to MEN2A.  Perhaps half of MEN2B cases occur sporadically and in these the mutant RET allele is usually of paternal origin.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

Treatment of local lesions is sometimes indicated.  Biochemical testing for pheochromocytoma should be done before any surgery.

References
Article Title: 

Charcot-Marie-Tooth Disease with Glaucoma

Clinical Characteristics
Ocular Features: 

Optic atrophy can be an ocular manifestation of CMT disease, especially in the X-linked forms, but this variant is the only one in which early-onset glaucoma is a feature.  It may begin at birth in some patients who have features of congenital glaucoma such as buphthalmos, while in other family members, including juveniles, only elevated intraocular pressures were reported.  Optic nerve damage seems to occur rapidly.

Systemic Features: 

This is a sensorineural disease of myelination that causes a polyneuropathy with muscular weakness and sensory deficits.  CMT4B2 is characterized by abnormal myelin sheath folding.  Symptoms of lower limb weakness and evidence of muscle atrophy commonly appear in the middle of the first decade with progression to upper limb involvement.  Areflexia follows with development of pes cavus and hammertoes.  Motor nerve conduction velocities may be severely reduced and muscle biopsies show severe loss of myelinated fibers and focal myelin sheath folding.

Genetics

This seems to be an autosomal recessive disorder although only a few families have been reported.  Homozygous mutations in the SBF2 gene (sometimes called MTMR13) (11p15.4) were found in these CMT families with early-onset glaucoma (604563).  This gene codes for SET binding factor 2 important to the normal development of the trabecular meshwork.  Not all SBF2 mutations cause glaucoma though.  Of course, it is possible that the occurrence of glaucoma is incidental and not part of CMT4B2 at all.

A clinically similar neurological condition without glaucoma, CMT4B1 (601382), has been reported to be caused by a mutation in MTMR2 located at 11q22 (601382). 

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Little is known about the natural history of the glaucoma in this condition but it occurs early and severe visual loss seems to be common.  Early diagnosis and vigorous treatment are important.  The neurological disease requires a multidisciplinary approach with physical therapists, neurologists, orthopedic surgeons and the use of prostheses.

References
Article Title: 

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
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