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Aspartylglucosaminuria

Aspartylglycosylaminase Defic

Aspartylglucosaminuria is a progressive genetic disorder belonging to the group of lysosomal storage diseases, with progressive mental retardation appearing in early infancy and childhood, being the main clinical feature. Additional symptoms involving the central nervous system, soft tissues, and various other organs may be evident. A thorough diagnostic workup is necessary in order to make the diagnosis.


Presentation

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].

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]
  • The hallmark of this lysosomal storage of oligosaccharides is progressive intellectual decline, markedly behavioral problems, hyperactivity, recurrent infections, epilepsy and facial dysmorphism, including coarse facies, macrocephalus and gingival hyperplasia[ncbi.nlm.nih.gov]
  • 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]
  • 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]
Family History of Mental Retardation
  • There was a family history of mental retardation in one male cousin, maternal uncle and maternal aunt (as indicated in the family tree in Figure 1 ). Family tree of the patients.[ncbi.nlm.nih.gov]
Aspiration
  • Two died of bronchopneumonia and 1 of asphyxiation following aspiration.[ncbi.nlm.nih.gov]
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]
Periodontitis
  • CONCLUSIONS: Patients with aspartylglucosaminuria appear to be at a higher risk for a number of oral disorders; however, poor oral hygiene and failure to cooperate increase these patients' risk of dental and periodontal diseases, making successful prevention[ncbi.nlm.nih.gov]
Poor Oral Hygiene
  • CONCLUSIONS: Patients with aspartylglucosaminuria appear to be at a higher risk for a number of oral disorders; however, poor oral hygiene and failure to cooperate increase these patients' risk of dental and periodontal diseases, making successful prevention[ncbi.nlm.nih.gov]
Anterior Open Bite
  • Tooth crown size and crown shape were normal, but dental malocclusions were common, and prevalences of spacing, large overjet, anterior open bite, and lateral crossbite exceeded Finnish population prevalences (P 0.0001).[ncbi.nlm.nih.gov]
Lordosis
  • 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)[symptoma.com]
Dermatitis
  • 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)[symptoma.com]
Facial Angiofibroma
  • Of 44 patients, nine (20%) had facial angiofibromas, tumours primarily occurring in association with tuberous sclerosis. Oedemic buccal mucosa (leucoedema) and gingival overgrowths were more frequent in AGU patients than in controls (p[ncbi.nlm.nih.gov]
Aggressive Behavior
  • New clinical phenomena were talipes planovalgus or clubfoot, needing surgical treatment, and aggressive behavior, needing, occasionally, child psychiatric consultation or treatment.[ncbi.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]
Seizure
  • Nocturnal video-polysomnography recorded several events consistent with a diagnosis of hypermotor epileptic seizures.[ncbi.nlm.nih.gov]
  • 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]
Confusion
  • This metabolic defect in glycoprotein catabolism can be clinically confused with other storage diseases such as the mucopolysaccharidoses and mucolipidoses. It is not diagnosed by routine laboratory screening methods.[ncbi.nlm.nih.gov]
  • […] 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[symptoma.com]

Workup

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].

Treatment

  • 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]
  • New clinical phenomena were talipes planovalgus or clubfoot, needing surgical treatment, and aggressive behavior, needing, occasionally, child psychiatric consultation or treatment.[ncbi.nlm.nih.gov]
  • 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]
  • 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]

Prognosis

  • 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

  • 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]

Epidemiology

  • 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.com]
Sex distribution
Age distribution

Prevention

  • 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]

References

Article

  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.

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Last updated: 2019-06-28 10:43