Mitochondrial DNA Depletion Syndrome 1 Clinical CharacteristicsOcular Features: Progressive external ophthalmoplegia has an adult onset, usually in the late second or early third decade of life. Ptosis is commonly present as well. Systemic Features: This condition has been called a mitochondrial neurogastrointestinal encephalopathy (MNGIE). Gastrointestinal problems are among the most disabling with poor absorption of foodstuffs leading to weight loss, marked cachexia, and chronic malnutrition. Added to this are gastroparesis, constipation, vomiting, and intermittent diarrhea with abdominal pain. Many individuals develop diverticulosis and diverticulitis that may lead to intestinal perforations. The combined intestinal dysfunctions can lead to signs of intestinal pseudoobstruction. Many patients have a progressive sensorineural hearing loss. Leukoencephalopathy, sensorimotor peripheral neuropathy, and sometimes mild proximal limb weakness may be present. GeneticsHomozygous and compound heterozygous mutations in the TYMP gene (22q13.33) are responsible for this autosomal recessive disorder. This nuclear gene is active in the maintainence of mitochondrial DNA. When the gene is dysfunctional, the mitochondria can be depleted to a variable extent and they may contain multiple deletions and point mutations. Pedigree: Autosomal recessiveTreatmentTreatment Options: There is no effective treatment for the overall condition. Nutritionists can provide important advice on diet to maintain good nutrition. Regular monitoring by gastroenterologists is important. Perforations of the bowels require prompt surgical repair. ReferencesArticle Title: Gastrointestinal dysmotility in mitochondrial neurogastrointestinal encephalomyopathy is caused by mitochondrial DNA depletion Giordano C, Sebastiani M, De Giorgio R, Travaglini C, Tancredi A, Valentino ML, Bellan M, Cossarizza A, Hirano M, d'Amati G, Carelli V. Gastrointestinal dysmotility in mitochondrial neurogastrointestinal encephalomyopathy is caused by mitochondrial DNA depletion. Am J Pathol. 2008 Oct;173(4):1120-8. PubMed ID: 18787099 Mitochondrial neurogastrointestinal encephalomyopathy: an autosomal recessive disorder due to thymidine phosphorylase mutations Nishino I, Spinazzola A, Papadimitriou A, Hammans S, Steiner I, Hahn CD, Connolly AM, Verloes A, Guimaraes J, Maillard I, Hamano H, Donati MA, Semrad CE, Russell JA, Andreu AL, Hadjigeorgiou GM, Vu TH, Tadesse S, Nygaard TG, Nonaka I, Hirano I, Bonilla E, Rowland LP, DiMauro S, Hirano M. Mitochondrial neurogastrointestinal encephalomyopathy: an autosomal recessive disorder due to thymidine phosphorylase mutations. Ann Neurol. 2000 Jun;47(6):792-800. PubMed ID: 10852545 Read more about Mitochondrial DNA Depletion Syndrome 1
Gastrointestinal dysmotility in mitochondrial neurogastrointestinal encephalomyopathy is caused by mitochondrial DNA depletion Giordano C, Sebastiani M, De Giorgio R, Travaglini C, Tancredi A, Valentino ML, Bellan M, Cossarizza A, Hirano M, d'Amati G, Carelli V. Gastrointestinal dysmotility in mitochondrial neurogastrointestinal encephalomyopathy is caused by mitochondrial DNA depletion. Am J Pathol. 2008 Oct;173(4):1120-8. PubMed ID: 18787099
Mitochondrial neurogastrointestinal encephalomyopathy: an autosomal recessive disorder due to thymidine phosphorylase mutations Nishino I, Spinazzola A, Papadimitriou A, Hammans S, Steiner I, Hahn CD, Connolly AM, Verloes A, Guimaraes J, Maillard I, Hamano H, Donati MA, Semrad CE, Russell JA, Andreu AL, Hadjigeorgiou GM, Vu TH, Tadesse S, Nygaard TG, Nonaka I, Hirano I, Bonilla E, Rowland LP, DiMauro S, Hirano M. Mitochondrial neurogastrointestinal encephalomyopathy: an autosomal recessive disorder due to thymidine phosphorylase mutations. Ann Neurol. 2000 Jun;47(6):792-800. PubMed ID: 10852545
Ataxia with Oculomotor Apraxia 2 Clinical CharacteristicsOcular 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. GeneticsHomozygous 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 recessiveTreatmentTreatment Options: There is no beneficial treatment for the neurological disease but physical therapy, speech therapy, and sometimes special education can be helpful. ReferencesArticle 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 Read more about Ataxia with Oculomotor Apraxia 2
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
Charcot-Marie-Tooth Disease with Glaucoma Clinical CharacteristicsOcular 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. GeneticsThis 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 recessiveTreatmentTreatment 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. ReferencesArticle Title: SET binding factor 2 (SBF2) mutation causes CMT4B with juvenile onset glaucoma Hirano R, Takashima H, Umehara F, Arimura H, Michizono K, Okamoto Y, Nakagawa M, Boerkoel CF, Lupski JR, Osame M, Arimura K. SET binding factor 2 (SBF2) mutation causes CMT4B with juvenile onset glaucoma. Neurology. 2004 Aug 10;63(3):577-80. PubMed ID: 15304601 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 Read more about Charcot-Marie-Tooth Disease with Glaucoma
SET binding factor 2 (SBF2) mutation causes CMT4B with juvenile onset glaucoma Hirano R, Takashima H, Umehara F, Arimura H, Michizono K, Okamoto Y, Nakagawa M, Boerkoel CF, Lupski JR, Osame M, Arimura K. SET binding factor 2 (SBF2) mutation causes CMT4B with juvenile onset glaucoma. Neurology. 2004 Aug 10;63(3):577-80. PubMed ID: 15304601
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
