dystonia

Dystonia, Childhood Onset, With Optic Atrophy

Clinical Characteristics
Ocular Features: 

Optic atrophy is often observed during the first decade of life and has been noted as early as 15 months.  It may be congenital.  Nystagmus has been seen in some patients.

Systemic Features: 

Signs of motor dysfunction are seen in the first decade of life, and as early as 15 months of age.  Motor development may be mildly delayed.  Features are variable and include facial dystonia, myoclonus, dyskinesia, dysarthria, dysphagia, limb spasticity, and chorea-like movements all of which may progress.  Some patients lose independent ambulation but cognition is not affected.

Brain imaging reveals hyperintense T2-weighted signals in the basal ganglia.

Genetics

The transmission pattern in 5 reported families is consistent with autosomal recessive inheritance.  Biallelic mutations in the MECR gene (1p35) have been found in 7 affected individuals.

This nuclear gene plays a role in mitochondrial fatty acid synthesis.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment has been reported.

References
Article Title: 

MECR Mutations Cause Childhood-Onset Dystonia and Optic Atrophy, a Mitochondrial Fatty Acid Synthesis Disorder

Heimer G, Keratar JM, Riley LG, Balasubramaniam S, Eyal E, Pietikainen LP, Hiltunen JK, Marek-Yagel D, Hamada J, Gregory A, Rogers C, Hogarth P, Nance MA, Shalva N, Veber A, Tzadok M, Nissenkorn A, Tonduti D, Renaldo F; University of Washington Center for Mendelian Genomics., Kraoua I, Panteghini C, Valletta L, Garavaglia B, Cowley MJ, Gayevskiy V, Roscioli T, Silberstein JM, Hoffmann C, Raas-Rothschild A, Tiranti V, Anikster Y, Christodoulou J, Kastaniotis AJ, Ben-Zeev B, Hayflick SJ. MECR Mutations Cause Childhood-Onset Dystonia and Optic Atrophy, a Mitochondrial Fatty Acid Synthesis Disorder. Am J Hum Genet. 2016 Dec 1;99(6):1229-1244.

PubMed ID: 
27817865

Neurodegeneration with Ataxia, Dystonia, and Gaze Palsy, Childhood-Onset

Clinical Characteristics
Ocular Features: 

Vertical gaze palsy has its onset between 7 and 15 years of age.   Nystagmus and oculomotor apraxia are often present.

Systemic Features: 

Onset of unsteadiness, gait ataxia, and cognitive decline are evident in the first or second decades of life.  Dysdiadokinesis, dysarthria, dysmetria, dystonia, athetotic movements, signs of Parkinsonism with tremor may also be present.  Some patients have a mild hearing loss.  Tissue from muscle biopsies are normal.  Brain imaging reveals cerebellar atrophy in some families and iron deposition in the basal ganglia in others.

Many patients are wheelchair-bound eventually.

Genetics

Homozygous mutations in the SQSTM1 gene (5q35.3) are responsible for this condition. 

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment has been reported but physical therapy, speech therapy, and special education may be of benefit.

References
Article Title: 

Absence of the Autophagy Adaptor SQSTM1/p62 Causes Childhood-Onset Neurodegeneration with Ataxia, Dystonia, and Gaze Palsy

Haack TB, Ignatius E, Calvo-Garrido J, Iuso A, Isohanni P, Maffezzini C, Lonnqvist T, Suomalainen A, Gorza M, Kremer LS, Graf E, Hartig M, Berutti R, Paucar M, Svenningsson P, Stranneheim H, Brandberg G, Wedell A, Kurian MA, Hayflick SA, Venco P, Tiranti V, Strom TM, Dichgans M, Horvath R, Holinski-Feder E, Freyer C, Meitinger T, Prokisch H, Senderek J, Wredenberg A, Carroll CJ, Klopstock T. Absence of the Autophagy Adaptor SQSTM1/p62 Causes Childhood-Onset Neurodegeneration with Ataxia, Dystonia, and Gaze Palsy. Am J Hum Genet. 2016 Sep 1;99(3):735-43.

PubMed ID: 
27545679

Coats Plus Syndrome

Clinical Characteristics
Ocular Features: 

Retinal telangiectasia and exudates (Coats disease) occur in association with intracranial cysts, calcifications and extraneurologic manifestations in this condition.  Coats disease lesions may also occur in Labrune syndrome (614561) and, of course, in isolation.

Whereas simple Coats disease almost exclusively occurs unilaterally and in males, both sexes and both eyes may have Coats retinal lesions in this syndrome.

Systemic Features: 

As a result of intracranial calcifications, leukodystrophy and brain cysts, patients have a variety of neurologic signs including spasticity, ataxia, dystonia, cognitive decline, and seizures.  Vascular ectasias may also occur throughout the body such as the intestines, stomach, and in the liver increasing the risk of GI bleeding and portal hypertension with anemia and thrombocytopenia.  Some individuals have sparse hair, abnormal pigmentation of the skin, and dysplastic nails as well. 

Some extraretinal features are also found in patients with dyskeratosis congenita (127550), and in Labrune syndrome (614561).

Genetics

This autosomal recessive pleotropic disorder results from compound heterozygous mutations in the CTC1 gene (17p13.1).  Several patients with mutations in STN1 have also been reported.

Most cases of simple Coats disease occur sporadically.  No associated locus or mutation has been found.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment for the general condition has been reported.  Specific treatment for the retinal vascular and brain lesions might be of benefit.  Physical therapy and special education should be considered in selected patients.

References
Article Title: 

Mutations in STN1 cause Coats plus syndrome and are associated with genomic and telomere defects. J Exp Med. 2016 Jul 25;213(8):1429-40

Simon AJ, Lev A, Zhang Y, Weiss B, Rylova A, Eyal E, Kol N, Barel O, Cesarkas K, Soudack M, Greenberg-Kushnir N, Rhodes M, Wiest DL, Schiby G, Barshack I, Katz S, Pras E, Poran H, Reznik-Wolf H, Ribakovsky E, Simon C, Hazou W, Sidi Y, Lahad A, Katzir H, Sagie S, Aqeilan HA, Glousker G, Amariglio N, Tzfati Y, Selig S, Rechavi G, Somech R. Mutations in STN1 cause Coats plus syndrome and are associated with genomic and telomere defects. J Exp Med. 2016 Jul 25;213(8):1429-40.

PubMed ID: 
27432940

Mutations in CTC1, encoding conserved telomere maintenance component 1, cause Coats plus

Anderson BH, Kasher PR, Mayer J, Szynkiewicz M, Jenkinson EM, Bhaskar SS, Urquhart JE, Daly SB, Dickerson JE, O'Sullivan J, Leibundgut EO, Muter J, Abdel-Salem GM, Babul-Hirji R, Baxter P, Berger A, Bonafe L, Brunstom-Hernandez JE, Buckard JA, Chitayat D, Chong WK, Cordelli DM, Ferreira P, Fluss J, Forrest EH, Franzoni E, Garone C, Hammans SR, Houge G, Hughes I, Jacquemont S, Jeannet PY, Jefferson RJ, Kumar R, Kutschke G, Lundberg S, Lourenco CM, Mehta R, Naidu S, Nischal KK, Nunes L, Ounap K, Philippart M, Prabhakar P, Risen SR, Schiffmann R, Soh C, Stephenson JB, Stewart H, Stone J, Tolmie JL, van der Knaap MS, Vieira JP, Vilain CN, Wakeling EL, Wermenbol V, Whitney A, Lovell SC, Meyer S, Livingston JH, Baerlocher GM, Black GC, Rice GI, Crow YJ. Mutations in CTC1, encoding conserved telomere maintenance component 1, cause Coats plus. Nat Genet. 2012 Jan 22;44(3):338-42.

PubMed ID: 
22267198

Cataracts, Congenital, Intellectual Disability, Abnormal Striatum, and ADHD

Clinical Characteristics
Ocular Features: 

Cataracts (not further described) were described as congenital although the diagnosis was usually made early in the first decade of life.  One patient was diagnosed at the age of 8 years with glaucoma and a cloudy cornea of the left eye.  Another patient had cataract surgery.  Visual acuities have not been reported.

Systemic Features: 

Four members of a consanguineous Saudi family have been reported with growth and mental retardation, microcephaly, dystonia, and spasticity.  IQs in the range of 77-89 were reported.  Linguistic delay is common.  Dysarthria and decreased cognitive function are present.  MRIs revealed thinning of the lentiform nucleus and swelling of the caudate heads.  

Genetics

Homozygous mutations in the KCNA4 (11p14.1) (176266) gene are responsible for this disorder.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment is available for the general condition.  Cataract surgery may be considered.

References
Article Title: 

KCNA4 deficiency leads to a syndrome of abnormal striatum, congenital cataract and intellectual disability

Kaya N, Alsagob M, D'Adamo MC, Al-Bakheet A, Hasan S, Muccioli M, Almutairi FB, Almass R, Aldosary M, Monies D, Mustafa OM, Alyounes B, Kenana R, Al-Zahrani J, Naim E, Binhumaid FS, Qari A, Almutairi F, Meyer B, Plageman TF, Pessia M, Colak D, Al-Owain M. KCNA4 deficiency leads to a syndrome of abnormal striatum, congenital cataract and intellectual disability. J Med Genet. 2016 Aug 31. pii: jmedgenet-2015-103637. doi: 10.1136/jmedgenet-2015-103637. [Epub ahead of print].

PubMed ID: 
27582084

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 2

Clinical Characteristics
Ocular Features: 

Horizontal nystagmus is present in some patients.

Systemic Features: 

Cerebellar ataxia, dysarthria, and spasticity of the lower limbs appear in the first two decades of life.  The spasticity may involve all 4 limbs late in life.  Cognition is not impacted. Cervical dystonia has been noted. No consistent changes have been found on brain imaging.  The neurologic signs are slowly progressive although patients may remain ambulatory.

Tremor, clonus, and extrapyramidal chorea has been seen in several families with what has been called spastic paraplegia-58 which may be the same disorder as SPAX2 since mutations are found in the same gene (KIF1C).  Symptoms and prognosis are similar in these conditions except for the reported presence of developmental delay and mild mental retardation in some individuals diagnosed to have SPG58.

Genetics

This is an autosomal recessive condition as the result of homozygous mutations in the KIF1C gene (17p13.2).

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No effective treatment for this disease is available although speech and physical therapy may be helpful.

References
Article Title: 

Motor protein mutations cause a new form of hereditary spastic paraplegia

Caballero Oteyza A, Battaloglu E, Ocek L, Lindig T, Reichbauer J, Rebelo AP, Gonzalez MA, Zorlu Y, Ozes B, Timmann D, Bender B, Woehlke G, Zuchner S, Schols L, Schule R. Motor protein mutations cause a new form of hereditary spastic paraplegia. Neurology. 2014 May 7. [Epub ahead of print].

PubMed ID: 
24808017

Exome sequencing links corticospinal motor neuron disease to common neurodegenerative disorders

Novarino G, Fenstermaker AG, Zaki MS, Hofree M, Silhavy JL, Heiberg AD, Abdellateef M, Rosti B, Scott E, Mansour L, Masri A, Kayserili H, Al-Aama JY, Abdel-Salam GM, Karminejad A, Kara M, Kara B, Bozorgmehri B, Ben-Omran T, Mojahedi F, Mahmoud IG, Bouslam N, Bouhouche A, Benomar A, Hanein S, Raymond L,Forlani S, Mascaro M, Selim L, Shehata N, Al-Allawi N, Bindu PS, Azam M, Gunel M, Caglayan A, Bilguvar K, Tolun A, Issa MY, Schroth J, Spencer EG, Rosti RO, Akizu N, Vaux KK, Johansen A, Koh AA, Megahed H, Durr A, Brice A, Stevanin G, Gabriel SB, Ideker T, Gleeson JG. Exome sequencing links corticospinal motor neuron disease to common neurodegenerative disorders. Science. 2014 Jan 31;343(6170):506-11.

PubMed ID: 
24482476

Ataxia with Oculomotor Apraxia 2

Clinical Characteristics
Ocular Features: 

Patients with this disorder have difficulty initiating voluntary ocular movements upon command or following targets (oculomotor apraxia).  This feature is not as prominent or frequent in AOA2 (56%) as it is in ataxia with oculomotor apraxia 1 (208920).  Gaze changes are often initiated first by head thrusting, followed by saccadic eye movements. One may test for this by holding the head whereupon the patient is unable to move the eyes.  Strabismus and nystagmus are present in a significant proportion of patients.  Optokinetic nystagmus is impaired.

Systemic Features: 

Initial development proceeds normally but cerebellar ataxia with significant gait problems appear toward the end of the first decade of life and sometimes not until the third decade (mean age of onset 15 years).   Distal muscle weakness and atrophy are often seen.  Mental decline has been observed in a few individuals but does not occur until midlife.  Sensorimotor deficits are present in many patients.  Tremors, dystonia, and choreiform movements are sometimes seen.  Many patients become wheelchair-bound by the 4th decade of life.

Cerebellar atrophy is revealed by MRI.  Serum alpha-fetoprotein concentrations are usually elevated while serum creatine kinase is increased in some patients.  Circulating cholesterol may also be above normal.  Mild serum changes in these components may be seen in heterozygotes.  Hypoalbuminemia is not present in AOA2.

Genetics

Homozygous mutations in SETX (9q34.13) are responsible for this disorder.  Ataxia with oculomotor apraxia 2 is distinguished from ataxia-telangiectasia (208900) by the lack of telangiectases and immunological deficiencies. It differs from ataxia with oculomotor apraxia 1 (208920) in having a somewhat later onset, somewhat slower course, and milder oculopraxic manifestations. Cogan-type oculomotor apraxia (257550) lacks other neurologic signs. Oculomotor apraxia may be the presenting sign in Gaucher disease (230800, 230900, 231000).

See also Ataxia with Oculomotor Apraxia 3 (615217), and Ataxia with Oculomotor Apraxia 4 (616267).

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

There is no beneficial treatment for the neurological disease but physical therapy, speech therapy, and sometimes special education can be helpful.

References
Article Title: 

Epidemiological, clinical, paraclinical and molecular study of a cohort of 102 patients affected with autosomal recessive progressive cerebellar ataxia from Alsace, Eastern France: implications for clinical management

Anheim M, Fleury M, Monga B, Laugel V, Chaigne D, Rodier G, Ginglinger E, Boulay C, Courtois S, Drouot N, Fritsch M, Delaunoy JP, Stoppa-Lyonnet D, Tranchant C, Koenig M. Epidemiological, clinical, paraclinical and molecular study of a cohort of 102 patients affected with autosomal recessive progressive cerebellar ataxia from Alsace, Eastern France: implications for clinical management. Neurogenetics. 2010 Feb;11(1):1-12.

PubMed ID: 
19440741

Ataxia with oculomotor apraxia type 2: a clinical, pathologic, and genetic study

Criscuolo C, Chessa L, Di Giandomenico S, Mancini P, Sacc?+ F, Grieco GS, Piane M, Barbieri F, De Michele G, Banfi S, Pierelli F, Rizzuto N, Santorelli FM, Gallosti L, Filla A, Casali C. Ataxia with oculomotor apraxia type 2: a clinical, pathologic, and genetic study. Neurology. 2006 Apr 25;66(8):1207-10.

PubMed ID: 
16636238

Wilson Disease

Clinical Characteristics
Ocular Features: 

The cornea and lens have visible copper deposition.  This is responsible for the classic (though non-pathognomonic) copper-colored Kayser-Fleischer ring in the cornea where evidence of copper deposition can be visualized in the posterior stroma and in the endothelium.  About 50-60% of patients at any point have evidence of such copper deposition but the number rises to 90% in patients with neurologic and psychiatric symptoms.  Copper deposition in the lens leads to a ‘sunflower’ or 'sunburst' cataract consisting of a greenish central disc in the anterior capsule with spoke-like radial cortical opacities.  Eye involvement in Wilson disease usually does not lead to significant impairment of vision.

Systemic Features: 

This is a disorder of copper metabolism.  It is associated with severe liver disease, often beginning with signs of recurrent jaundice, sometimes a hepatitis-like illness, and often culminating in liver failure.  Hepatobiliary malignancies are a significant risk, occurring in more than 1 percent of patients.  Neurologic toxicity leads to various movement disorders such as tremors, poor coordination, dystonia, and choreoathetosis.  Many patients have mental symptoms such as depression, neurotic behavior, and personality disturbances.  Some have a mask-like facies and pseudobulbar symptoms.  Symptoms can appear anytime from 3 years of age to over 50.  Other organs such as kidney, pancreas, heart and even joints may also be involved.

Patients often have a low serum ceruloplasmin, low copper levels, increased urinary excretion of copper, and increased concentration of copper in the liver.

Genetics

This is an autosomal recessive disorder caused by homozygous or doubly heterozygous mutations in the ATP7B gene (13q14.3).  Heterozygotes usually do not develop symptoms but may have reduced serum ceruloplasmin levels.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Zinc and/or copper chelating agents such as D-penicillamine or trientine have long been used with benefit but the treatment must be used throughout life.  Reduced copper intake may also be helpful.  An orthotopic liver transplant can prolong life in selected patients.

References
Article Title: 

Hepatobiliary malignancies in Wilson disease.

Pfeiffenberger J, Mogler C, Gotthardt DN, Schulze-Bergkamen H, Litwin T, Reuner U, Hefter H, Huster D, Schemmer P, Czlonkowska A, Schirmacher P, Stremmel W, Cassiman D, Weiss KH. Hepatobiliary malignancies in Wilson disease. Liver Int. 2014 Nov 4. [Epub ahead of print].

PubMed ID: 
25369181

A practice guideline on Wilson disease

Roberts EA, Schilsky ML; Division of Gastroenterology and Nutrition, Hospital for Sick Children, Toronto, Ontario, Canada. A practice guideline on Wilson disease. Hepatology. 2003 Jun;37(6):1475-92. Erratum in: Hepatology. 2003 Aug;38(2):536.

PubMed ID: 
12774027

Neurodegeneration with Brain Iron Accumulation

Clinical Characteristics
Ocular Features: 

Optic atrophy is a major ocular feature and the primary cause of visual impairment.  A minority (25%) of patients also have a diffuse fleck retinopathy with a bull’s eye maculopathy.  Later the retinopathy may resemble retinitis pigmentosa with a bone spicule pattern. Nystagmus is often present.  These signs usually follow systemic signs such as difficulties in locomotion.  An apraxia of eyelid opening has been noted and some patients have blepharospasm. 

Systemic Features: 

This is a progressive disorder of the basal ganglia with prominent symptoms of extrapyramidal dysfunction.  Onset is in early childhood or in the neonatal period with delayed development and sometimes mental retardation.  Choreoathetoid writhing movements, stuttering, dysphagia, muscle rigidity, and intermittent dystonia are prominent features.  Seizures are uncommon.  Older individuals may exhibit dementia and ambulation is eventually impaired.  The MRI usually shows an area of hyperintensity in the medial globus pallidus that has been called the ‘eye of the tiger’ sign but this is not pathognomonic.  Axonal degeneration with accumulation of spheroidal inclusions can be seen histologically. 

Genetics

The title of this disorder ‘neurodegeneration with brain iron accumulation’ actually refers to a group of disorders with somewhat common characteristics.  Pentothenate kinase-associated neurodegeneration or NB1A1 (234200) is  the most common of these. 

Types  NBIA2A (256600) and NBIA2B (610217) are caused by mutations in the PLA2G6 gene (22q13.1).  The former can be seen neonatally but usually has its onset in the first two years of life and is sometimes called infantile neuroaxonal dystrophy or Seitelberger disease.  Death may occur before the age of 10 years.  Signs of motor neuron and cerebellar disease are more prominent than in NB1A1. 

NBIA2B has a later onset (4-5 years) and profound sensorimotor impairment but there are many overlapping features and the nosology is confusing.  Mutations in the FTL gene cause yet another form designated NBIA3 (606159) but ocular signs seem to be absent. 

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

There is evidence that treatment with deferiprone reduces the amount of iron accumulation in the globus pallidus with motor improvement in at least some patients.  Most patients require supportive care.

References
Article Title: 

Pantothenate Kinase-Associated Neurodegeneration

Clinical Characteristics
Ocular Features: 

Clinically evident retinal degeneration is present in a significant number (25-50%) of individuals.  However, when combined with ERG evidence the proportion rises to 68%.  When present it occurs early and one series reported that it is unlikely to appear later if it was not present early in the course of the neurodegeneration.  Some patients have a fleck-like retinopathy.  Optic atrophy may be present in advanced cases.

Systemic Features: 

This is a disorder primarily of the basal ganglia resulting from progressive damage secondary to iron accumulation.  There is an early onset classic form with symptoms of extrapyramidal disease beginning in the first decade of life and rapid progression to loss of ambulation in about 15 years.  Others with atypical disease may not have symptoms until the second or third decades.  Clumsiness, gait disturbance, and difficulty with tasks requiring fine motor coordination are common presenting symptoms.  Motor tics are often seen.  Dysarthria, dystonia, rigidity and corticospinal signs are often present early as well.  Swallowing difficulties may be severe sometimes leading to malnutrition.  Cognitive decline and psychiatric disturbances such as obsessive-compulsive behavior and depression may follow.  Independent ambulation is lost in the majority of patients within one to two decades.    Brain MRIs show an ‘eye of the tiger’ sign with a specific T2- weighted pattern of hyperintensity within the medial globus pallidus and the substantia nigra pars reticulata.

Genetics

Iron accumulation in the basal ganglia resulting from homozygous mutations in the PANK2 gene (20p13-12.3) encoding a pantothenate kinase leads to the classic form of this autosomal recessive disorder. 

This is the most common of several diseases of neurodegeneration with iron accumulation in the brain known collectively as NBIAs.  The group is genetically heterogeneous with many overlapping features.  Mutations in PLA2G6 cause NBIA2A (256600) and NBIA2B (610217) while mutations in a FLT gene cause NBIA3 (606159). The latter does not have apparent eye signs.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Pharmacologic treatment is aimed at alleviation of specific symptoms such as dystonia and spasticity.  Some symptoms may improve with deep brain stimulation.

References
Article Title: 

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