Arginemia

Arginemia (also called arginase deficiency) is a congenital disorder where arginase deficiency causes a high level of arginine and ammonia in the blood. Ammonia, which is formed when proteins are broken down in the body, is toxic if levels become too high. The nervous system is especially sensitive to the effects of excess ammonia.

Arginase deficiency usually becomes evident by about the age of 3. It most often appears as stiffness, especially in the legs, caused by abnormal tensing of the muscles (spasticity). Other symptoms may include slower than normal growth, developmental delay and eventual loss of developmental milestones, mental retardation, seizures, tremor, and difficulty with balance and coordination (ataxia). Occasionally, high protein meals or stress caused by illness or periods without food (fasting) may cause ammonia to accumulate more quickly in the blood. This rapid increase in ammonia may lead to episodes of irritability, refusal to eat, and vomiting.

In some affected individuals, signs and symptoms of arginase deficiency may be less severe, and may not appear until later in life.

Mutations in the ARG1 gene cause arginase deficiency. Arginase deficiency belongs to a class of genetic diseases called urea cycle disorders. The urea cycle is a sequence of reactions that occurs in liver cells. This cycle processes excess nitrogen, generated when protein is used by the body, to make a compound called urea that is excreted by the kidneys.

The ARG1 gene provides instructions for making an enzyme called arginase. This enzyme controls the final step of the urea cycle, which produces urea by removing nitrogen from arginine. In people with arginase deficiency, arginase is damaged or missing, and arginine is not broken down properly. As a result, urea cannot be produced normally, and excess nitrogen accumulates in the blood in the form of ammonia. The accumulation of ammonia and arginine are believed to cause the neurological problems and other signs and symptoms of arginase deficiency.

Arginase deficiency is inherited in an autosomal recessive pattern.

This condition is inherited in an autosomal recessive pattern, which means two copies of the gene in each cell are altered. Most often, the parents of an individual with an autosomal recessive disorder are carriers of one copy of the altered gene but do not show signs and symptoms of the disorder.

Differential diagnosis

Arginase deficiency must be differentiated from other diseases that cause neurological manifestations in infants.

Diseases	Type of motor abnormality				Clinical findings	Laboratory findings and diagnostic tests	Radiographic findings
Diseases	Spasticity	Hypotonia	Ataxia	Dystonia	Clinical findings	Laboratory findings and diagnostic tests	Radiographic findings
Leigh syndrome	–	–	+	+	Progressive psychomotor regression Seizures External ophthalmoplegia Lactic acidosis Vomiting	Increased lactate levels in blood and CSF Genetic testing	MRI: abnormal white matter signal in the putamen, basal ganglia, and brainstem on T2 images
Niemann-Pick disease type C	–	–	+	+	Progressive neurodegeneration Hepatosplenomegaly Systemic involvement of liver, spleen, or lung preceedes neurologic symptoms	Abnormal liver function tests Fibroblast cell culture with filipin staining	MRI: Cerebral and cerebellar atrophy Thinning of the corpus callosum
Infantile Refsum disease	–	+	+	–	Abnormalities of the optic nerve and disc Retinitis pigmentosa Sensorineural hearing loss Hepatomegaly and cirrhosis Neurologic deterioration is slower than in Zellweger syndrome or ALD	Elevated plasma VLCFA levels	—
Adrenoleukodystrophy	+	–	–	–	Cognitive and behavioral abnormalities Adrenal insufficiency Hyperpigmented skin Gonadal dysfunction Neurologic deterioration progresses at a variable rate	Elevated plasma VLCFA levels Molecular genetic testing for mutations in the ABCD1 gene	—
Zellweger syndrome	–	+	–	–	Craniofacial dysmorphism Hepatomegaly Neonatal seizures Profound developmental delay MRI findings include cortical and white matter abnormalities Neurologic deterioration is rapid and infants rarely survive beyond six months of age	Elevated plasma VLCFA levels Elevated levels of phytanic acid, pristanic acid, and pipecolic acid in plasma and fibroblasts Reduced plasmalogen in erythrocytes Molecular genetic testing for mutations in the PEX1 or PEX6 genes	—
Pyruvate dehydrogenase deficiency	+	+	+	–	Lactic acidosis Seizures Intellectual disability	Elevated lactate and pyruvate levels in blood and CSF Abnormal PDH enzymatic activity in cultured fibroblasts	—
Arginase deficiency	+	–	–	–	Hyperammonemia Encephalopathy Respiratory alkalosis	Elevated ammonia level Elevated arginine level	—
Holocarboxylase synthetase deficiency	–	+	–	–	Ketoacidosis Dermatitis Alopecia Seizures Developmental delay	Elevated levels of: Beta-hydroxyisovalerate Beta-methylcrotonylglycine Beta-hydroxypropionate Methylcitrate Tiglylglycine	—
Glutaric aciduria type 1	–	–	–	+	Episodes of metabolic decompensation and encephalopathy often precipitated by infection and fever Rarely presents in the newborn period Microencephalic macrocephaly Seizures (approximately 20 percent) Cognitive function is preserved	Elevated levels of: glutaric acid 3-hydroxyglutaric acid	MRI: Frontal and temporal atrophy
Ataxia telangiectasia	–	–	+	–	Progressive cerebellar ataxia Abnormal eye movements Oculocutaneous telangiectasias Immune deficiency Increased risk of malignancy	Elevated serum alpha-fetoprotein level Low IgA and IgG levels Lymphopenia Genetic testing for mutation in the ATM gene	—
Pontocerebellar hypoplasias	–	+	–	–	Progressive muscle atrophy Microcephaly Developmental delay	Genetic testing for PCH gene mutations	MRI : Small cerebellum and brainstem including the pons
Metachromatic leukodystrophy	–	+	+	–	Regression of motor skills Seizures Optic atrophy Reduced or absent deep tendon reflexes Intellectual disability	Deficient arylsulfatase A enzyme activity in leukocytes or cultured skin fibroblasts	—
Pelizaeus-Merzbacher	+	–	+	–	Nystagmus Cognitive impairment Onset in infancy Slowly progressive Language development may be normal	Genetic testing for mutations in PLP1 gene	MRI: White matter abnormalities
Angelman syndrome	–	–	+	–	Profound intellectual disability Postnatal microcephaly Typical abnormal behaviors (paroxysmal laughter, easily excitable)	Methylation studies and chromosome microarray to detect chromosome 15 anomalies and UBE3A mutations	—
Rett syndrome	+	–	–	+	Occurs almost exclusively in females Normal development during first six months followed by regression and loss of milestones Loss of speech capability Stereotypic hand movements Seizures Autistic features	Clinical diagnosis Genetic testing for MECP2 mutations	—
Lesch-Nyhan syndrome	+	–	–	+	Self-mutilating behavior Urinary stones due to hyperuricemia	Elevated uric acid level Abnormal enzymatic activity of HPRT in cultured fibroblasts Genetic testing for HPRT gene mutations	—
Miller-Dieker lissencephaly	+	+	–	–	Lissencephaly Microcephaly Dysmorphic features Seizures Failure to thrive	Cytogenetic testing for 17p13.3 microdeletion	—
Dopa-responsive dystonia	+	–	–	+	Onset in early childhood Symptoms worsen with fatigue and exercise	Positive response to a trial of levodopa	—

References

Arginemia at NLM Genetics Home Reference

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Arginemia

Differential diagnosis

References

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