lactic acidosis

Mitochondrial DNA Depletion Syndrome 1

Clinical Characteristics
Ocular 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.

Genetics

Homozygous 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 recessive
Treatment
Treatment 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.  

References
Article Title: 

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

Mitochondrial DNA Depletion Syndrome 3

Clinical Characteristics
Ocular Features: 

Nystagmus, disconjugate eye movements, and "optic dysplasia" have been noted.

Systemic Features: 

Infants feed poorly which is frequently associated with vomiting, failure to thrive, and growth delay.  They are hypothermic, hypoglycemic, and often jaundiced with signs of liver failure noted between birth and 6 months of age and death by approximately 1 year of age.  Hepatosplenomegaly is present early with abnormal liver enzymes, cholestasis, steatosis, and hepatocellular loss followed by cirrhosis with portal hypertension.  Metabolic acidosis, hyperbilirubinemia, hypoalbuminemia, and hypoglycemia are often present.  Mitochondrial DNA depletion in the liver approaches 84-90%.

All patients have encephalopathic signs with evidence of cerebral atrophy, microcephaly, hypotonia.  Hyperreflexia may be present and some infants have seizures.  Muscle tissue, however, has normal histology and respiratory chain activity.

Genetics

This disorder results from homozygous or compound heterozygous mutations in the DGUOK gene (2p13).

The same gene is mutated in PEOB4 (617070).

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

There is no effective treatment.  Liver transplantation in one infant was unsuccessful.  

References
Article Title: 

Fructose Intolerance

Clinical Characteristics
Ocular Features: 

Dense cataracts have been reported in the first decade of life in several patients.

Systemic Features: 

Abdominal pain, vomiting and hypoglycemia usually appears in infancy upon the introduction of fructose or sucrose to the diet.  Some infants have a more severe reaction to such sugars with lethargy, seizures and coma.  Older children and adults develop a protective aversion to fruits and sweets.  Chronic ingestion leads to liver cirrhosis, renal tubule damage, growth retardation, and even malnutrition.  Adults may also have hypoglycemia and metabolic acidosis when challenged with sucrose and fructose.

Genetics

This is an autosomal recessive disorder resulting from mutations in the ALDOB gene (9q31.1).  However, several heterozygous patients with symptoms have been reported and such individuals may be predisposed to hyperuricemia.  Multiple mutations have been identified in the ALDOB gene.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Treatment with a fructose restricted diet is highly effective but must be strictly enforced to allow normal growth.

References
Article Title: 

Hereditary fructose intolerance

Ali M, Rellos P, Cox TM. Hereditary fructose intolerance. J Med Genet. 1998 May;35(5):353-65. Review.

PubMed ID: 
9610797

Sengers Syndrome

Clinical Characteristics
Ocular Features: 

This is a mitochondrial DNA depletion syndrome in which congenital cataracts are the hallmark ocular feature.  The bilateral lens opacification is usually total at birth or within the first few weeks of life as manifested by leucocoria. Lens extraction is necessary within the first 6 months of life but visual rehabilitation is nearly always compromised postoperatively by nystagmus and strabismus.  In one series only one eye recovered to 20/40 but the average postoperative acuity was in the range of 20/200 and virtually all students require special education in schools for the visually impaired.  Axial myopia is common with most patients having myopic fundus changes and requiring less than +10 diopters of aphakic correction.  Pale optic disks and a pigmentary retinopathy were noted among 8 of 18 eyes in one series.  Mild and inconsistent dyschromatopsia has been reported in a few patients.  The ERG sometimes shows diminished rod and cone function.

Systemic Features: 

Hypertrophic cardiomyopathy is often diagnosed within a fews days after birth but 40% may escape detection until the second or third decade of life.  It is usually progressive and often fatal in the neonatal period.  Myopathy involves both cardiac and skeletal muscles.  Generalized hypotonia, exercise intolerance, and delayed motor development are important features in the majority of patients.  Metabolic lactic acidosis occurs with relatively minimal excercise.  Skeletal muscle biopsies show ragged-red fibers with combined deficiencies of mitochondrial complexes I, III, and IV along with severe depletion of mtDNA.  Increased urine levels of 3-methylglutaconic have been reported.

The central nervous system is usually not involved and mental development is normal if lactic acidosis is controlled.  However, several children with mental retardation have been reported.

Genetics

Homozygous or compound heterozygous mutations in AGK (7p34), a lipid metabolism gene, are responsible for this condition.  There is considerable variation in the severeity of the phenotypic features but no ocular or cardiac disease has been found in heterozygotes. 

The same gene was found to be mutated in an autosomal recessive congenital cataract (614691) in a single reported sibship. Thorough systemic evaluation found no evidence of cardiac and skeletal muscle disease.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Surgical removal of cataracts may be indicated.

References
Article Title: 

Lack of the mitochondrial protein acylglycerol kinase causes Sengers syndrome

Mayr JA, Haack TB, Graf E, Zimmermann FA, Wieland T, Haberberger B, Superti-Furga A, Kirschner J, Steinmann B, Baumgartner MR, Moroni I, Lamantea E, Zeviani M, Rodenburg RJ, Smeitink J, Strom TM, Meitinger T, Sperl W, Prokisch H. Lack of the mitochondrial protein acylglycerol kinase causes Sengers syndrome. Am J Hum Genet. 2012 Feb 10;90(2):314-20.

PubMed ID: 
22284826

MELAS Syndrome

Clinical Characteristics
Ocular Features: 

This progressive mitochondrial disorder primarily affects muscles and the CNS, including the visual system.  The pattern of ocular deficits is not consistent and those that are present are not specific, requiring the clinician to take the entire neurological picture into consideration.  Hemianopsia, cortical blindness and ophthalmoplegia may be present.  The ERG can show reduced b-wave amplitudes and VEPs may be absent.  The optic nerve head has been described as normal without the atrophy often seen with other mitochondrial disorders.  A pigmentary retinopathy may be present.

Systemic Features: 

The clinical picture is highly variable.  Most commonly patients have myopathy, encephalopathy, lactic acidosis, and stroke-like episodes.  The onset of symptoms is usually in the first two decades of life, most commonly consisting of headaches of sudden onset accompanied by vomiting and seizures.  The headaches may simulate migraines.  Weakness, lethargy, and apathy may be present early.  However, infants and young children may present with failure to thrive, developmental delay, and learning disabilities.  Neurosensory deafness is often seen and peripheral neuropathy is usually evident.  MRIs may show cerebellar hypoplasia and infarctions in the cerebral hemispheres.  Some patients have calcifications in the basal ganglia.  Patients may develop lactic acidosis.  Muscle biopsies often show ragged, red fibers.  The heart is commonly involved with both structural and rhythm defects.  Depending upon the degree and location of brain damage, patients may have hemiparesis, lethargy, ataxia, myoclonic jerks, cognitive decline, and dementia.  Morbidity and mortality are high.

Genetics

MELAS syndrome is a group of disorders caused by mutations in mitochondrial genes (at least 9 have been identified) that alter transfer RNA molecules resulting in disruption of intramitochondrial synthesis of proteins involved in oxidative phosphorylation pathways.  It is both clinically and genetically heterogeneous.  One can expect that any familial occurrence would result from maternal transmission but the occurrence of heteroplasmy results in considerable variability in the severity of clinical disease.

Treatment
Treatment Options: 

There is no effective treatment that prevents development of disease or that slows its progress.

References
Article Title: 
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