APA (Old Order Amish; Eastern Pennsylvania)

Inheritance: autosomal recessive
Genes: GCDH

GA I
Glutaric acidemia
Glutaryl-CoA dehydrogenase deficiency
Glutaric aciduria I

Seizures
Spasticity
Brainstem dysfunction
Choreoathetosis
Retinal hemorrhages
Mental retardation
Striatal necrosis
Bulbar palsy

Glutaric Aciduria, Type I

Clinical Characteristics

General description (for patients):

Glutaric aciduria type 1 (GA1) is an inherited disorder in which the body lacks a specific enzyme needed to break down certain amino acids.  Patients with the undiagnosed condition are sometimes lumped into the generic category of “cerebral palsy”.  Onset is generally in the first year of life and may be precipitated by an acute infectious illness. Signs of acute brain injury occur episodically, and when combined with hemorrhages in the retina may be misdiagnosed as child abuse.  The greatest risk of brain damage seems to be during early childhood.  Damage to the brainstem may be severe enough to cause death in young children.  Other signs include spasticity and purposeless writhing movements.  Impaired intellectual development sometimes occurs.  Not all patients are similarly affected, with some individuals having mild symptoms while others have more severe problems.

Medical description:  

GA I is classified as a disorder of organic acid metabolism caused by deficiency of the enzyme glutaryl CoA-dehydrogenase , a mitochondrial matrix enzyme needed in the breakdown pathway of the amino acids lysine, tryptophan and hydroxylysine.  GA I was originally identified as a cause of familial Amish cerebral palsy in Lancaster County, Pennsylvania.  Phenotypic expression is broad but in general the greatest risk to brainstem damage is during early childhood.  An enlarged head circumference may be the presenting sign.  An acute infectious illness sometimes precipitates an encephalopathy with signs of brain stem damage.  Combined with the presence of retinal hemorrhages, young patients may be misdiagnosed as victims of child abuse.  A small number of patients present in adolescence or adulthood with spasticity and bulbar palsies.  MR or CT imaging at birth typically shows an underdeveloped neocortex and diffuse expansion of the CSF space although the gyral pattern appears normal. Hypoplasia of the frontal lobes may be accompanied by an underdeveloped intermediate fiber zone and thin corpus callosum. The combination of hypoplastic brain structures and communicating hydrocephalus creates a distinctive radiological appearance that may be a pathognomonic feature of GA I.  Fluid collections in the medial cranial fossae can be substantial. Veins become stretched across this space and are subject to distortion and rupture leading to the encephalopathy. 

Hemodynamic studies have shown decreased capillary blood velocity  with reduced cerebral perfusion pressure resulting in venous congestion. In combination with metabolic toxicity, this often leads to stroke-like putaminal necrosis and basal ganglia degeneration resulting in the most distinctive and crippling manifestations of GA1.  Flaccidity, jerking, muscle spasms and dystonic posturing may be seen. The dystonia can interfere with talking, swallowing, airway reflexes, breathing and voluntary movements. Abnormal muscular contractions distort the developing skeleton and can dislocate joints.  Intelligence is relatively preserved if injury is confined to the putamen. Patients with caudate degeneration, however, have significant cognitive dysfunction. Confirmatory diagnosis is based on the measurement of organic acids such as glutaric acid which is elevated, while levels of 3-hydroxyglutarate, and glutarylcarnitine in urine samples although can vary widely.

Genetics:

GA I is an autosomal recessive disorder caused by mutations in the glutaryl CoA-dehydrogenase (GCDH) gene located on chromosome 19 (19p13.2).  The GCDH founder mutation among the Lancaster Amish is a C-to-T change (c.2362C>T) within exon 11 that causes an A-to-V change at amino acid 421 for which the majority of Amish patients are homozygous. Recently, a variant, G3, (231690) has been reported in three healthy Eastern PA Amish children who were homozygous for a sequence variant (c.895C>T) in C7orf10 containing a coenzyme-A transferase domain on chromosome 7.  Other mutations have been identified among non-Amish patients in other countries.

Treatment:

Dystonia in GA I is difficult to treat as medications that normally act on striatal receptors tend to be ineffective.  Maintenance of good hydration and vigorous treatment of infections can be critical during the first two years of life.  A low protein diet (to limit lysine and tryptophan intake) with L-carnitine supplementation may be helpful.

Prognosis:

A majority of patients are diagnosed after the development of striatal necrosis and prognosis for these patients is poor. Respiratory problems are the major cause of early mortality. In addition, despite progress overall, current therapy remains inadequate and morbidity is high among patients with dystonia.

Ancillary treatments and support:

Sedatives and muscle relaxants such as diazepam may be helpful for spasticity and movement disorders.  Disease–specific prophylactic care and the aggressive management of childhood illnesses improve outcome and reduce the incidence of striatal necrosis.  It has been suggested that good hydration and dextrose therapy for acute illnesses, especially in the first two years of life, may be neuroprotective.

Specialists and specialty centers:

References:

Morton, D. H.; Bennett, M. J.; Seargeant, L. E.; Nichter, C. A.; Kelley, R. I.:  Glutaric aciduria type I: a common cause of episodic encephalopathy and spastic paralysis in the Amish of Lancaster County, Pennsylvania. Am. J. Med. Genet. 41: 89-95, 1991.  PubMed ID: 1951469

Strauss, K.A., Puffenberger, E.G., Robinson, D.L. and Morton, D.H.: Type 1 glutaric aciduria, part 1: natural history of 77 patients. Am. J. Med. Genet. 121:38-52, 2003. PubMed ID: 12888985

Strauss, K.A., Lazovic, J., Wintermark, M., and Morton, D.H.:  Multmodal imaging of striatal degeneration in Amish patients with glutary-CoA dehydrogenase deficiency.  Brain 130: 1905-1920, 2007.  PubMed ID: 17478444

Sherman, E.A., Strauss, K.A., Tortorelli, S., Bennett, M.J., Knerr, I., Morton, D.H., and Puffenberger, E.G.: Genetic mapping of glutaric aciduria, type 3, to chromosome 7 and identification of mutations in C7orf10.  Am. J. Hum. Genet. 83(5):604-609, 2008. PubMed ID: 18926513

Strauss, K.A., Donnelly, P., and Wintermark, M.:  Cerebral haemodynamics in patients with glutaryl-coenzyme A dehydrogenase deficiency.  Brain: Epub ahead of print, Dec 23, 2009.  PubMed ID: 20032085

Resources:

Clinic for Special Children, Strasburg, PA
Organic Acidemia Association

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