Symptoms in aspartylglucosaminuria arise due to the deficiency of the enzyme aspartylglucosaminidase (AGA), an essential component in the process of oligosaccharide degradation [1]. Consequently, accumulation of oligosaccharides (specifically glycoasparagine) in various body tissues, primarly the central nervous system occurs, which is why mental retardation, developing in the first several years of life, is the most prominent clinical feature [2] [3]. The diagnosis is most frequently made between 5-6 years of age [2]. The decline of mental functions is progresses slowly throughout puberty and early adulthood, with rapid deterioration after 30 years of age and life expectancy is usually below 45 years of age [4] [5]. Progression seems to be slower in females, and due to the founder effect, this autosomal recessive condition is almost exclusively seen in the Finnish population [2] [5] [6]. An increased head circumference that shrinks with age (due to slow decay of brain cells) and a growth spurt during infancy are two most common accompanying signs, whereas the appearance of hernias, recurrent respiratory infections, delayed speech and cognitive development, gingival hyperplasia, and facial coarsening is reported as well [2] [4] [7]. Additional musculoskeletal (thickening of the ribs and skull, lordosis, vertebral dysplasia, contractures in fingers and elbows, a knock knee, muscle atrophy and hypotonia) and cutaneous (angiokeratomas, erythema and seborrheic dermatitis on the face) signs may be encountered, while many patients experience psychotic symptoms, restlessness, confusion and other psychiatric manifestations [2] [3] [4] [5]. Moreover, hepatosplenomegaly, cardiomyopathy, and macroorchidism, but also epilepsy and abnormal paroxysmal motor events during sleep can comprise the clinical presentation of aspartylglucosaminuria [2] [7]. In approximately 7% of cases, joint involvement is observed, mainly in the form of chronic arthritis [5].

• Disability

  The team for habilitation should include professionals who are experienced in disabilities and the effects that having a disability can have on everyday life. [en.wikipedia.org]

  Mild intellectual disability then becomes apparent, and learning occurs at a slowed pace. Intellectual disability progressively worsens in adolescence. [ghr.nlm.nih.gov]

• Developmental Delay

  Aspartylglucosaminuria (AGU) is characterized by developmental delay and intellectual disability that worsens with age. [clinicaltrials.gov]

  It is characterized by developmental delays during childhood.,MSH: A recessively inherited, progressive lysosomal storage disease caused by a deficiency of GLYCOSYLASPARAGINASE activity. [linkedlifedata.com]

  Around the age of 2–4 years, they begin showing signs of developmental delay, but development is still progressing. Initial symptoms may present as clumsiness and/or speech delay. [ismrd.org]

• Weakness

  Pre- and perinatal histories appeared normal for all children, except for muscular hypotonia and weak sucking in some babies. Three infants had abduction stiffness in the hips, needing follow-up. [ncbi.nlm.nih.gov]

  People with this condition may also have bones that become progressively weak and prone to fracture ( osteoporosis ), an unusually large range of joint movement (hypermobility), and loose skin. [ghr.nlm.nih.gov]

  Adults with aspartylglucosaminuria may develop seizures or problems with movement. [3] People with this condition may also have bones that become progressively weak and prone to fracture ( osteoporosis ), an unusually large range of joint movement ( hypermobility [rarediseases.info.nih.gov]

• Recurrent Infection

  Most of the reported cases have been in Finland. as·par·tyl·gly·cos·a·mi·nu·ri·a ( as-par'til-glī-kō'să-min-yū'rē-ă ) [MIM*208400] A lysosomal disorder caused by deficiency of aspartoglucosaminidase; involves recurrent infections and diarrhea; mental [medical-dictionary.thefreedictionary.com]

  Clincal signs and symptoms include hepatomegaly, splenomegaly, hearing loss, mental retardation, skeletal abnormalities, and recurrent respiratory infections. [icd10data.com]

  Recurrent infections are also common. Patients may also have problems with their bones, such as abnormalities in the curvature of their spine and in their facial features. [zymenex.com]

  He also had a past surgical history of myringotomy due to recurrent ear infections. [ncbi.nlm.nih.gov]

• Short Stature

  stature Decreased body height Small stature [ more ] 0004322 Spasticity Involuntary muscle stiffness, contraction, or spasm 0001257 Spondylolisthesis Displacement of one backbone compared to another Slipped backbone [ more ] 0003302 Spondylolysis 0003304 [rarediseases.info.nih.gov]

• Diarrhea

  208400] A lysosomal disorder caused by deficiency of aspartoglucosaminidase, resulting in accumulation of aspartylglycosamine in the urine and spinal fluid; characterized by symptoms usually in the first few months of life, with recurrent infections and diarrhea [medical-dictionary.thefreedictionary.com]

  Episodic diarrhea, described earlier, appeared to be a rather infrequent symptom and a less valuable diagnostic clue. [ncbi.nlm.nih.gov]

  Less severe symptoms include: enlargement of the spleen and liver diarrhea People with aspartylglucosaminuria may have lower than average height, because they tend to go through puberty earlier. Epilepsy may develop in adulthood. [en.wikipedia.org]

• Vomiting

  Symptoms include irritability, unexplained fever, limb stiffness, seizures, feeding difficulties, vomiting, and slowing of mental and motor development. Other symptoms include muscle weakness, spasticity, deafness, and blindness. [zymenex.com]

• Macroglossia

  To our knowledge, macroglossia with a scrotal appearance and polycystic ovarian disease have not been reported in previous cases of AGU. [ncbi.nlm.nih.gov]

  Features of AGU include progressive intellectual disability, characteristic facial features and body structure (i.e. microcephaly, coarse facies, low nasal bridge, macroglossia, and delayed skeletal maturation), recurrent childhood respiratory tract infections [egl-eurofins.com]

  The infantile form (type i) features psychomotor deterioration, muscle spasticity, coarse facial features, growth retardation, skeletal abnormalities, visceromegaly, seizures, recurrent infections, and macroglossia, with death occurring in the first decade [icd10data.com]

  Abnormal cortical bone morphology 0003103 Abnormality of the ulna 0002997 Anterior beaking of lumbar vertebrae 0008430 Carious teeth Dental cavities Tooth cavities Tooth decay [ more ] 0000670 Coarse facial features Coarse facial appearance 0000280 Macroglossia [rarediseases.info.nih.gov]

• Osteoporosis

  People with this condition may also have bones that become progressively weak and prone to fracture ( osteoporosis ), an unusually large range of joint movement (hypermobility), and loose skin. [ghr.nlm.nih.gov]

  Facial features may coarsen, vertebral and long bone changes may be seen on x-ray, and osteoporosis may occur in adults with AGU. Some patients experience seizures. [ismrd.org]

  Affected adults may have seizures, movement disorders, osteoporosis, hypermobility, and loose skin. Macrocephaly may be present in children, while adults have microcephaly. The average life span of patients is usually less than 50 years. [genedx.com]

  […] features and body structure (i.e. microcephaly, coarse facies, low nasal bridge, macroglossia, and delayed skeletal maturation), recurrent childhood respiratory tract infections, psychiatric problems during adolescence, seizures, chronic arthritis, and osteoporosis [egl-eurofins.com]

• Hypertelorism

  A consistent dysmorphic gestalt with hypertelorism, a short and broad nose with round nares, simple often small ears with small or missing lobule and modest folding of helices, thick lips and a square shape of face, was found to be present long before [ncbi.nlm.nih.gov]

  Affected individuals tend to have a characteristic facial appearance that includes widely spaced eyes ( ocular hypertelorism ), small ears, and full lips. The nose is short and broad and the face is usually square-shaped. [ghr.nlm.nih.gov]

• Thick Lips

  A consistent dysmorphic gestalt with hypertelorism, a short and broad nose with round nares, simple often small ears with small or missing lobule and modest folding of helices, thick lips and a square shape of face, was found to be present long before [ncbi.nlm.nih.gov]

  […] vermilion border Full lips Increased volume of lip Plump lips Prominent lips Thick lips [ more ] 0012471 Umbilical hernia 0001537 Wide nasal bridge Broad nasal bridge Broad nasal root Broadened nasal bridge Increased breadth of bridge of nose Increased [rarediseases.info.nih.gov]

• Seizure

  Nocturnal video-polysomnography recorded several events consistent with a diagnosis of hypermotor epileptic seizures. [ncbi.nlm.nih.gov]

  […] caused by deficiency of aspartoglucosaminidase, resulting in accumulation of aspartylglycosamine in the urine and spinal fluid; characterized by symptoms usually in the first few months of life, with recurrent infections and diarrhea; mental retardation, seizures [medical-dictionary.thefreedictionary.com]

  Treatment is supportive and involves management of symptoms, including medications for frequent infections and seizures, and surgeries to repair problems related to loose joints. [web.archive.org]

A detailed patient history is the first and fundamental step for the diagnosis of aspartylglucosaminuria. Although pregnancy, perinatal period and early infancy are uneventful [2], the onset of mental retardation and accompanying facial, skeletal or other notable features in individuals of Finnish ancestry must prompt the physician to exclude this lysosomal storage disease as a possible cause [6]. More importantly, a complete family history may reveal similar findings in siblings or close relatives (due to the autosomal recessive pattern of inheritance), while consanguineous marriages are also an important risk factor [2] [4]. After a detailed physical examination and confirmation of central nervous system complaints, magnetic resonance imaging (MRI) of the endocranium, a procedure that solidifies its importance when it comes to the diagnosis of aspartylglucosaminuria, is recommended, and will show hyperintensity of white matter and hypointensity of the thalamus on T2-weighed images, as well as brain atrophy [2] [8]. On the other hand, laboratory investigations in the form of urine and serum testing is a more specific diagnostic method, comprised of detection of oligosaccharides and subsequent molecular analysis that will determine the activity of glycosylasparaginase, an enzyme necessary for their degradation [2] [4]. Finally, genetic testing to confirm mutations in the aspartylglucosaminidase (AGA) gene on chromosome 4q32-q33.1 is performed, and in the setting of a known mutation in one or both parents, a prenatal diagnosis from chorionic villus or amniotic fluid samples can be achieved [2] [4].

• Neutropenia

  0002808 Microcephaly Abnormally small skull Decreased circumference of cranium Decreased size of skull Reduced head circumference Small head circumference [ more ] 0000252 Mitral regurgitation 0001653 Muscular hypotonia Low or weak muscle tone 0001252 Neutropenia [rarediseases.info.nih.gov]

The uniform phenotype observed in these patients will make effective evaluation of treatment trials feasible in future. [ncbi.nlm.nih.gov]

Genetic counseling Transmission is autosomal recessive Management and treatment The only attempt of curative treatment to this day is allogenic bone marrow grafting, but the results in 5 Finnish patients were limited. [orpha.net]

Currently there is no treatment available but a group of families have joined together and created Rare Trait Hope Fund to develop a treatment for AGU Medical and research information • Aspartylglucosaminuria review by Professor Ritva Tikkanen, updated [ismrd.org]

Diagnosis - Aspartylglycosaminuria Prognosis - Aspartylglycosaminuria Individuals with AGU typically have normal development in infancy. [checkorphan.org]

Prognosis [ edit ] Individuals with AGU typically have normal development in infancy. Around the age of 2–4 years, they begin showing signs of developmental delay, but development is still progressing. [en.wikipedia.org]

Etiology AGU is caused by mutations in gene AGU located on 4q34.3. [orpha.net]

The family, with a strong suspicion for a genetic etiology, utilized a commercially available genome sequencing platform to identify a region of interest within chromosome 4. [onlinelibrary.wiley.com]

Rare Disease Epidemiology – 2nd Edition In mid-2017, John was invited to write a preface for a book called Rare Diseases Epidemiology, which concentrates on the work done for LDNZ and ISMRD and talks about what patient advocates can achieve. [ldnz.org.nz]

Summary Epidemiology AGU is only exceptionally found outside of Finland. [orpha.net]

Chapters on epidemiology, embryology, non-syndromic hearing loss, and syndromic forms of hearing loss have all been updated with particular attention to the vast amount of new information on molecular mechanisms, and chapters on clinical and molecular [books.google.ro]

Both this and a previously characterized Finnish AGU mutation appear to affect folding of the single-chain precursor of glycosylasparaginase and thereby prevent transport of the enzyme to lysosomes. [ncbi.nlm.nih.gov]

AGA gene mutations result in the absence or shortage of the aspartylglucosaminidase enzyme in lysosomes, preventing the normal breakdown of glycoproteins. As a result, glycoproteins can build up within the lysosomes. [ghr.nlm.nih.gov]

1. Opladen T, Ebinger F, Zschocke J, et al. Aspartylglucosaminuria: unusual neonatal presentation in Qatari twins with a novel aspartylglucosaminidase gene mutation and 3 new cases in a Turkish family. J Child Neurol. 2014;29(1):36-42.
2. Arvio M, Mononen I. Aspartylglycosaminuria: a review. Orphanet J Rare Dis. 2016;11:162.
3. Longo DL, Fauci AS, Kasper DL, Hauser SL, Jameson J, Loscalzo J. eds. Harrison's Principles of Internal Medicine, 18e. New York, NY: McGraw-Hill; 2012.
4. Tokola AM, Åberg LE, Autti TH. Brain MRI findings in aspartylglucosaminuria. J Neuroradiol. 2015;42(6):345-357.
5. Arvio M, Laiho K, Kauppi M, et al. Carriers of the aspartylglucosaminuria genetic mutation and chronic arthritis. Ann Rheum Dis. 2002;61(2):180-181.
6. Porter RS, Kaplan JL. Merck Manual of Diagnosis and Therapy. 19th Edition. Merck Sharp & Dohme Corp. Whitehouse Station, N.J; 2011.
7. Ambrosetto G, Santucci M. Sleep-related hypermotor seizures in aspartylglucosaminuria: a case report. Epilepsia. 2009;50(6):1638-1640.
8. Sui L, Lakshminarasimhan D, Pande S, Guo H-C. Structural basis of a point mutation that causes the genetic disease Aspartylglucosaminuria. Structure. 2014;22(12):1855-1861.