neuropathy

Spastic Paraplegia, Optic Atrophy, and Neuropathy

Clinical Characteristics
Ocular Features: 

Non-progressive optic atrophy with vision loss is described as congenital in onset.

Systemic Features: 

Progressive spasticity has its onset in infancy with loss of independent mobility usually in the second decade of life.  An exaggerated startle response occurs in some individuals.  All patients are confined to wheelchairs after 15 years of age due to progressive motor neuropathy.  No intellectual disability has been reported.  Joint contractures occur.  Dysarthria is notable in the third decade of life.  Eventually joint contractures and spine deformities occur.

Genetics

Homozygous mutations in the KLC2 gene (11q13.2) have been found in this disorder.  A homozygous 216-bp deletion in a non-coding region upstream of the gene results in overexpression of the gene not found in heterozygotes.  

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment has been described.

References
Article Title: 

Overexpression of KLC2 due to a homozygous deletion in the non-coding region causes SPOAN syndrome

Melo US, Macedo-Souza LI, Figueiredo T, Muotri AR, Gleeson JG, Coux G, Armas P, Calcaterra NB, Kitajima JP, Amorim S, Olavio TR, Griesi-Oliveira K, Coatti GC, Rocha CR, Martins-Pinheiro M, Menck CF, Zaki MS, Kok F, Zatz M, Santos S. Overexpression of KLC2 due to a homozygous deletion in the non-coding region causes SPOAN syndrome. Hum Mol Genet. 2015 Dec 15;24(24):6877-85.

PubMed ID: 
26385635

Optic Atrophy, Ophthalmoplegia, Myopathy, and Neuropathy

Clinical Characteristics
Ocular Features: 

Visual symptoms have an insidious onset in childhood with vision loss and progressive external ophthalmoplegia.  Ptosis may be evident later.  The optic atrophy is progressive.   ERG abnormalities have been reported but no pigmentary retinopathy has been seen.  Myopia is sometimes present.

Systemic Features: 

The extraocular signs and symptoms are variable and generally have a later onset.  Some patients have an early onset of sensorineural hearing loss.  Muscle cramps and hyperreflexia may occur with clonus and a spastic gait.  Ataxia seems to be common.  The neurological phenotype has been likened to muscular sclerosis, Kearns-Sayre syndrome, and spastic paraplegia.  Muscle biopsies show variable-sized and atrophic fibers.

Genetics

This is generally considered an autosomal dominant disorder secondary to mutations in the OPA1 gene.  It is allelic to optic atrophy 1 (165500) but may also be the same condition since the p.Arg247His mutation has been found in patients with both disorders.  This syndromic form of optic atrophy may also result from biallelic mutations in OPA1 in which the clinical disease is more severe and earlier in onset. 

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

No treatment is available for the neurological disease but low vision aids should be considered to selected patients especially during childhood educational activities.

References
Article Title: 

Multi-system neurological disease is common in patients with OPA1 mutations

Yu-Wai-Man P, Griffiths PG, Gorman GS, Lourenco CM, Wright AF, Auer-Grumbach M, Toscano A, Musumeci O, Valentino ML, Caporali L, Lamperti C, Tallaksen CM, Duffey P, Miller J, Whittaker RG, Baker MR, Jackson MJ, Clarke MP, Dhillon B, Czermin B, Stewart JD, Hudson G, Reynier P, Bonneau D, Marques W Jr, Lenaers G, McFarland R, Taylor RW, Turnbull DM, Votruba M, Zeviani M, Carelli V, Bindoff LA, Horvath R, Amati-Bonneau P, Chinnery PF. Multi-system neurological disease is common in patients with OPA1 mutations. Brain. 2010 Mar;133(Pt 3):771-86.

PubMed ID: 
20157015

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

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.  Mutations (8993T-G) have been found in subunits 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

Hyperoxaluria, Primary, Type I

Clinical Characteristics
Ocular Features: 

About 30% of patients with type I develop retinopathy and about half of those have a diffuse optic atrophy.  Oxalate crystal deposition can cause a 'fleck retina' picture sometimes described as a crystalline retinopathy.  There is wide variation in the retinal phenotype.  Retinal toxicity leads to early and progressive vision loss.  The RPE may respond with hyperpigmentation in the form of 'ringlets' in the posterior pole.  Retinal fibrosis has been described.  Some patients develop choroidal neovascularization.

Evaluation using EDI-OCT shows progressive deposition of oxalate crystals throughout the retina, pigment epiithelium, and choroid.

Systemic Features: 

The onset of this disease can occur any time from infancy to 25 years of age.  Failure to thrive can be a presenting sign in infants.  Most patients have glycolic aciduria and hyperoxaluria as the result of failure to transaminate glyoxylate to form glycine.  The result is deposition of insoluble oxalate crystals in various body tissues with nephrolithiasis and nephrocalcinosis often early signs.  Neurologic, cardiac, vascular, and kidney disease is often the result although oxalate crystals can be found throughout the body.  Arteriole occlusive disease may lead to gangrene, Raynaud phenomena, acrocyanosis and intermittent claudication.  Renal failure is common. 

Genetics

Hyperoxaluria type I is an autosomal recessive disorder resulting from a mutation in the alanine-glyoxylate aminotransferase gene (AGXT) located at 2q36-q37.  Failure of this liver peroxisomal enzyme to transaminate glyoxylate results in oxidation of this molecule to form oxalate.

Hyperoxaluria type II (260000) is caused by mutations in the GRHPR gene (9cen) and type III (613616) by mutations in DHDPSL (HOGA1) (10q24.2).  Urolithiasis is the only clinical feature in these types. 

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Some patients benefit from oral pyridoxine (B6) treatment in type I hyperoxaluria.  Renal transplantation by itself is only temporarily helpful since the enzymatic defect remains and the donor tissue becomes damaged as well.  Combined renal-liver transplantation should be considered instead because it corrects the primary metabolic error and can even reverse the accumulation of oxalate crystals. 

References
Article Title: 

Primary hyperoxaluria in infants

Jellouli M, Ferjani M, Abidi K, Zarrouk C, Naija O, Abdelmoula J, Gargah T. Primary hyperoxaluria in infants. Saudi J Kidney Dis Transpl. 2016 May-Jun;27(3):526-32.

PubMed ID: 
27215245

Primary hyperoxaluria

Cochat P, Rumsby G. Primary hyperoxaluria. N Engl J Med. 2013 Aug 15;369(7):649-58. Review.

PubMed ID: 
23944302

Marinesco-Sjogren Syndrome

Clinical Characteristics
Ocular Features: 

Congenital cataracts are one of the cardinal features of Marinesco-Sjogren syndrome but lens opacities may have a later onset and may be progressive as well.  Strabismus and nystagmus are sometimes present.

Systemic Features: 

Non-ocular features include cerebellar atrophy, psychomotor developmental delays, mental retardation, and muscle weakness.  Dysarthria is common.  The myopathy has its onset in childhood and is progressive with weakness, hypotonia, and atrophy eventually leading to total disability in some cases.  Progression of motor dysfunction may, however, stabilize in some patients but at an unpredictable level.  Infants are often 'floppy babies'.  MRI studies reveal cerebellar atrophy.  Serum creatine kinase levels are increased and muscle biopsies show chronic myopathic changes.  Skeletal features include short stature, pectus carinatum, and secondary kyphoscoliosis and foot deformities.  Bone abnormalities may be seen in the digits.

Genetics

This is an autosomal recessive condition resulting from mutations in the SIL1 gene (5q31).  It is sometimes confused with the condition known as congenital cataracts, facial dysmorphism, and neuropathy (604168) with which it shares some clinical features.  The two conditions are genetically distinct since they are caused by mutations in different genes.

See also Muscular Dystrophy, Congenital Cataracts, with Cataracts and Intellectual Disability for a similar disorder caused by a different mutation.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Visually significant cataracts may need to be removed in the first decade of life.  Skeletal deformities may benefit from surgery and hormone therapy should be considered in specific cases.

References
Article Title: 

The gene disrupted in Marinesco-Sjögren syndrome encodes SIL1, an HSPA5 cochaperone

Anttonen AK, Mahjneh I, Hamalainen RH, Lagier-Tourenne C, Kopra O, Waris L, Anttonen M, Joensuu T, Kalimo H, Paetau A, Tranebjaerg L, Chaigne D, Koenig M, Eeg-Olofsson O, Udd B, Somer M, Somer H, Lehesjoki AE. The gene disrupted in Marinesco-Sjogren syndrome encodes SIL1, an HSPA5 cochaperone. Nat Genet. 2005 Dec;37(12):1309-11.

PubMed ID: 
16282978

Linkage to 18qter differentiates two clinically overlapping syndromes: congenital cataracts-facial dysmorphism-neuropathy (CCFDN) syndrome and Marinesco-Sjogren syndrome

Lagier-Tourenne C, Chaigne D, Gong J, Flori J, Mohr M, Ruh D, Christmann D, Flament J, Mandel JL, Koenig M, Dollfus H. Linkage to 18qter differentiates two clinically overlapping syndromes: congenital cataracts-facial dysmorphism-neuropathy (CCFDN) syndrome and Marinesco-Sjogren syndrome. J Med Genet. 2002 Nov;39(11):838-43.

PubMed ID: 
12414825

Cataracts, Congenital, Facial Dysmorphism, and Neuropathy

Clinical Characteristics
Ocular Features: 

Cataracts, microphthalmia, and microcornea (mean diameter ~7.5 mm) are present at birth and precede the onset of neurological symptoms.  The lens opacities often consist of anterior and posterior subcapsular opacities but the entire lens may be opaque as well.  Some adults have bilateral ptosis.  The pupils are often small and have sluggish responses to light and mydriatics.  Strabismus and horizontal pendular nystagmus are common.  Visual impairment may be severe.

Systemic Features: 

The neuropathy is primarily motor and usually begins in the lower extremities but is progressive and eventually involves the arms as well.  Motor development is slow and walking is often unsteady from the start.  Speaking may not have its onset until 3 years of age.   Mild, nonprogresssive cognitive defects and mental retardation are often present.  Sensory neuropathy with numbness and tingling develops in the second decade.  Mild chorea, upper limb tremor, mild ataxia, and extensor plantar responses may be seen.  Deafness has been described.  Nerve conduction studies and biopsies have documented a demyelinating polyneuropathy while MRIs demonstrate cerebral and spinal cord atrophy which may be seen in the first decade of life.  The MRI in many patients reveals diffuse cerebral atrophy, enlargement of the lateral ventricles and focal lesions in subcortical white matter.  Most individuals have mild cognitive deficits while psychometric testing reveals borderline intelligence in a minority.

Patients are susceptible to acute rhabdomyolysis following viral infections.  Most are severely disabled by the third decade.

The facial dysmorphism appears in childhood and consists of a prominent midface, hypognathism, protruding teeth, and thickening of the lips.  Spinal deformities occur in the majority of individuals along with foot and hand claw deformities.  All patients are short in stature.  Hypogonadotropic hypogonadism is a common feature and females may be infertile.  Amenorrhea is often present by the age of 25-35 years.

Genetics

This is an autosomal recessive disorder found primarily among European Gypsies.  It is caused by mutations in the CTDP1 gene (18q23-qter).  It is sometimes confused with Marinesco-Sjogren syndrome (248800) with which it shares some clinical features but the two are genetically distinct.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Cataracts often require removal in the first decade of life. Scoliosis and foot deformities may benefit from surgical correction.  Supportive care and physical therapy can be helpful.

References
Article Title: 

Linkage to 18qter differentiates two clinically overlapping syndromes: congenital cataracts-facial dysmorphism-neuropathy (CCFDN) syndrome and Marinesco-Sjogren syndrome

Lagier-Tourenne C, Chaigne D, Gong J, Flori J, Mohr M, Ruh D, Christmann D, Flament J, Mandel JL, Koenig M, Dollfus H. Linkage to 18qter differentiates two clinically overlapping syndromes: congenital cataracts-facial dysmorphism-neuropathy (CCFDN) syndrome and Marinesco-Sjogren syndrome. J Med Genet. 2002 Nov;39(11):838-43.

PubMed ID: 
12414825

Congenital cataracts facial dysmorphism neuropathy syndrome, a novel complex genetic disease in Balkan Gypsies: clinical and electrophysiological observations

Tournev I, Kalaydjieva L, Youl B, Ishpekova B, Guergueltcheva V, Kamenov O, Katzarova M, Kamenov Z, Raicheva-Terzieva M, King RH, Romanski K, Petkov R, Schmarov A, Dimitrova G, Popova N, Uzunova M, Milanov S, Petrova J, Petkov Y, Kolarov G, Aneva L, Radeva O, Thomas PK. Congenital cataracts facial dysmorphism neuropathy syndrome, a novel complex genetic disease in Balkan Gypsies: clinical and electrophysiological observations. Ann Neurol. 1999 Jun;45(6):742-50.

PubMed ID: 
10360766

External Ophthalmoplegia, C10ORF2 and mtDNA Mutations

Clinical Characteristics
Ocular Features: 

Ptosis and external ophthalmoplegia are found in almost all patients.  These have a variable onset with some patients not symptomatic until midlife or later.  External ophthalmoplegia may be the only symptom.  Onset in late adolescence has also been reported.  Cataracts often occur.

Systemic Features: 

About half (52%) of patients have fatigue and weakness.  Ataxia and peripheral neuropathy with paresthesias are sometimes present. Some patients report bulbar symptoms of dysphagia, dysarthria and dysphonia.  Skeletal muscle biopsies show typical ragged red fibers and evidence of mitochondrial dysfunction with cytochrome c oxidase (COX) deficiency.  Late onset of typical features of parkinsonism including a resting tremor, rigidity, and bradykinesia is seen in some patients.  Several individuals have reported major depression and/or bipolar disorder. Myopathy (33%) with muscle wasting and respiratory difficulties can occur.   As many as 24% of patients have cardiac abnormalities consisting primarily of conduction defects.

Genetics

This an autosomal dominant disorder secondary to mutations in the C10ORF2 (Twinkle) gene (10q24) in association with mitochondrial DNA depletion.  It accounts for approximately 35% of autosomal dominant cases of external ophthalmoplegia.

At least two additional mutations cause similar external ophthalmoplegia syndromes: PEOA1 (157640, 258450), and PEOA2 (609283).

The same gene may have mutations that are responsible for spinocerebellar ataxia, infantile-onset (271245), a more generalized and progressive neurodegenerative disease transmitted in an autosomal recessive pattern.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

No effective treatment is known.

References
Article Title: 

The clinical, histochemical, and molecular spectrum of PEO1(Twinkle)-linked adPEO

Fratter C, Gorman GS, Stewart JD, Buddles M, Smith C, Evans J, Seller A, Poulton J, Roberts M, Hanna MG, Rahman S, Omer SE, Klopstock T, Schoser B, Kornblum C, Czermin B, Lecky B, Blakely EL, Craig K, Chinnery PF, Turnbull DM, Horvath R, Taylor RW. The clinical, histochemical, and molecular spectrum of PEO1(Twinkle)-linked adPEO. Neurology. 2010 May 18;74(20):1619-26.

PubMed ID: 
20479361

Corneal Dystrophy, Lattice Type II

Clinical Characteristics
Ocular Features: 

This is a systemic amyloidosis disorder with significant corneal disease.  The corneal stroma contains linear deposits which are more discrete, more peripheral, more delicate, and more radial than those in lattice type I with which it is sometimes confused.  There is also less accumulation of amorphous amyloid material than in type I.  The onset is often later as well, and rarely seen in childhood.  Corneal sensitivity is reduced.  Vision is less affected than in type I lattice dystrophy and patients rarely require keratoplasty, and, if so, later in life.

Amyloid deposits are found in the cornea, sclera, choroid, lacrimal gland, ciliary nerves, and adnexal blood vessels.  Ptosis and extraocular muscle dysfunction is not significant.

Systemic Features: 

Amyloid deposits are found throughout the body including blood vessels, heart, kidney, skin and nerves.  A "mask-like" facies with a protruding lower lip, dry itchy skin, peripheral and cranial neuropathy, and renal failure are clinical features but often have their onset late in life.  Facial paralysis and bulbar palsy may be the result.

Genetics

While this is considered an autosomal dominant disorder, presumed homozygous cases have been reported in Finland where the first cases were described.  These cases seem to have more severe disease with an earlier onset than found among patients with heterozygous mutations.  Mutations in the GSN gene located at 9q34 are responsible.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

Penetrating keratoplasty can be beneficial but is rarely needed for visual rehabilitation.  The amyloid deposits may recur in the donor tissue.  The reduced corneal sensitivity secondary to neural involvement increases the risk of post-operative neurotrophic epithelial defects.

References
Article Title: 

Hereditary gelsolin amyloidosis

Kiuru-Enari S, Haltia M. Hereditary gelsolin amyloidosis. Handb Clin Neurol. 2013;115:659-81. PubMed PMID: 23931809.

PubMed ID: 
23931809
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