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Aspartylglucosaminuria (AGU) is mainly found in Finland; the major pathogenic variants are approximately 50 times more frequent in Finns than non-Finnish Europeans. Outside of Finland, sporadic cases are observed, with > 50 known cases.

Clinical signs of AGU include slowly progressing neurodevelopmental disorder, beginning with clumsiness, delayed speech, and hyperkinesia. Patients also present with mild facial dysmorphism, and slight kyphoscoliosis. Hepatosplenomegaly is rare and has only been reported in non-Finnish cases.

AGU is caused by pathogenic variants of the AGA gene located on 4q34.3. In Finland, two major mutations have been described (AGU-fin major and AGU-fin minor) and account for more than 98% of disease alleles; systematic screening for heterozygous individuals would thus be possible. Outside of Finland, the disease-causing variants are heterogeneous and often family-specific. The pathogenic variants lead to a deficiency of aspartylglucosaminidase (AGA), an enzyme that cleaves the N-acetylglucosamine-asparagine bond found in N-glycosyled proteins. AGA deficiency causes excess accumulation of glycoasparagines in the tissues and body fluids, with an increased excretion in urine.

Most cases are detected by genetic analysis of the AGA gene or by exome sequencing. Biochemically, AGU is characterized by measuring the increased urinary excretion of aspartylglucosamine by liquid chromatography/mass spectrometry. A low activity of AGA enzyme can be measured in the serum, lymphocytes, fibroblasts, amniocytes or trophoblasts.

As glycoasparagines can also be sporadically detected in the urine of patients with NGLY1 deficiency, genetic analysis and AGA activity measurement should be used to verify the diagnosis.

Prenatal diagnosis by gene/exome sequencing or AGA enzyme activity measurement are possible.

Transmission is autosomal recessive. Genetic counseling should be offered to at-risk couples (both individuals are carriers of a disease-causing variant), informing them that there is a 25% risk of having an affected child at each pregnancy.

Older patients may become severely handicapped due to cognitive and physical decline and will require special care. Attempts of curative treatment with allogenic bone marrow grafting showed limited results in five Finish patients. In addition, hematopoietic stem cell transplantation in three non-Finnish AGU patients showed that the intervention needs to be performed early in life to slow down cognitive decline. Treatment with a pharmacological chaperone (trimethylglycine) is currently under clinical evaluation.

Patients show a profound cognitive and physical decline after the age of 20-25 years. Death usually occurs before the age of 50, but the oldest Finnish patients have survived over 60 years.