Chapter 10

INHERITED METABOLIC DISORDERS

DISORDERS OF AMINO ACID METABOLISM

This is a group of inherited defects of the degradation of amino acids. They include the urea cycle disorders, in which the defect involves conversion of the amino group to urea, and many of the organic acidemias, which are caused by defects in the disposal of the carbon skeletons of the branched chain amino acids after the initial transamination step. With the exception of ornithine transcarbamylase deficiency, which is X-linked, all amino acid disorders are autosomal recessive.

Clinical findings. Most amino acid disorders present in the neonatal period with a severe or fatal metabolic encephalopathy, which mimics perinatal asphyxia and sepsis. This encephalopathy is caused by the toxic effects of the accumulating amino acids and their intermediates, hyperammonemia, impairment of energy and synthetic pathways, and defective synthesis of neurotransmitters. The metabolic encephalopathy is often accompanied by respiratory depression, seizures, and hypoxic-ischemic brain injury. Survivors have psychomotor retardation, and suffer from recurrent neurotoxic episodes, which are triggered by metabolic stress, e.g., infections. The clinical picture in older patients resembles cerebral palsy. Less severe mutations cause milder illness, which presents later in life with developmental delay, episodes of metabolic decompensation, seizures, and ataxia. A few amino acid disorders (phenylketonuria, homocystinuria) have an insidious onset and a chronic course.

Pathological changes. Many amino acid and organic acid disorders are associated with spongy myelinopathy (SM). This is a poorly understood, non-progressive lesion of central myelin, characterized by fluid filled vacuoles in the myelin sheath, which impart a spongy appearance to the white matter.


Spongy myelinopathy

Spongy myelinopathy in nonketotic hyperglycinemia


Alzheimer type II astrocytes

Alzheimer type II astrocytes (large clear nuclei) in citrullinemia


Homocystinuria

Cortical infarct in a 20 year old patient with homocystinuria

Instability of myelin due to abnormal lipid composition of cell membranes may play a role in the pathogenesis of SM. Some amino acid disorders have different neuropathological lesions. Thus, Alzheimer type II astrocytes are seen in the urea cycle disorders, and vascular lesions are the key finding in homocystinuria. Hypoxic and ischemic changes (cortical and basal ganglia atrophy) are also seen in several amino acid disorders.

The clinical, biochemical, and pathological findings in the most common amino acid disorders are summarized in the table below.

Nonketotic hyperglycinemia
(defects of the glycine cleavage system)
Elevated glycine in plasma and CSF
Neonatal encephalopathy, psychomotor retardation
Spongy myelinopathy, agenesis of the corpus callosum
Urea cycle disorders
(5 enzymes of the urea cycle)
Hyperammonemia
Seizures Neonatal encephalopathy
Brain swelling, Alzheimer type II astrocytes
Maple Syrup Urine Disease
(defects of branched-chain ketoacid dehydrogenase complex)
Accumulation of branched-chain amino acids and their ketoacids
Neonatal encephalopathy, psychomotor retardation
Brain swelling, spongy myelinopathy
Homocystinuria
(cystathionine beta synthase deficiency)
Elevated homocysteine
Thrombosis, Marfanoid habitus, dislocation of lens
Venous and arterial thrombosis and cerebral infarcts

Top of Page