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Alpha-N-acetylgalactosaminidase deficiency type 2

MedGen UID:
324539
Concept ID:
C1836522
Disease or Syndrome
Synonyms: Alpha-N-acetylgalactosaminidase deficiency adult onset; ALPHA-N-ACETYLGALACTOSAMINIDASE DEFICIENCY, TYPE II; Kanzaki disease; NAGA deficiency type 2; NAGA DEFICIENCY, TYPE II; Schindler disease type 2; SCHINDLER DISEASE, TYPE II
SNOMED CT: Alpha-N-acetylgalactosaminidase deficiency type 2 (880065001); Schindler disease type 2 (880065001); NAGA (alpha-N-acetylgalactosaminidase) deficiency type 2 (880065001)
Modes of inheritance:
Autosomal recessive inheritance
MedGen UID:
141025
Concept ID:
C0441748
Intellectual Product
Source: Orphanet
A mode of inheritance that is observed for traits related to a gene encoded on one of the autosomes (i.e., the human chromosomes 1-22) in which a trait manifests in individuals with two pathogenic alleles, either homozygotes (two copies of the same mutant allele) or compound heterozygotes (whereby each copy of a gene has a distinct mutant allele).
 
Gene (location): NAGA (22q13.2)
 
Monarch Initiative: MONDO:0012222
OMIM®: 609242
Orphanet: ORPHA79280

Definition

Alpha-N-acetylgalactosaminidase (NAGA) deficiency is a very rare lysosomal storage disorder with atypical features. It is clinically heterogeneous with 3 main phenotypes: type I is an infantile-onset neuroaxonal dystrophy (609241); type II, also known as Kanzaki disease, is an adult-onset disorder characterized by angiokeratoma corporis diffusum and mild intellectual impairment; and type III is an intermediate disorder (see 609241) with mild to moderate neurologic manifestations (Desnick and Schindler, 2001). [from OMIM]

Additional description

From MedlinePlus Genetics
Schindler disease is an inherited disorder that primarily causes neurological problems.

Schindler disease type III is intermediate in severity between types I and II. Affected individuals may exhibit signs and symptoms beginning in infancy, including developmental delay, seizures, a weakened and enlarged heart (cardiomyopathy), and an enlarged liver (hepatomegaly). In other cases, people with this form of the disorder show neurodevelopmental problems beginning in early childhood, with some features of autism spectrum disorder. Autism spectrum disorder is characterized by impaired communication and socialization skills.

There are three types of Schindler disease. Schindler disease type I, also called the infantile type, is the most severe form. Babies with Schindler disease type I appear healthy at birth, but by the age of 8 to 15 months they stop developing new skills and begin losing skills they had already acquired (developmental regression). As the disorder progresses, affected individuals develop blindness and seizures, and eventually they lose awareness of their surroundings and become unresponsive. People with this form of the disorder usually do not survive past early childhood.

Schindler disease type II, also called Kanzaki disease, is a milder form of the disorder that usually appears in adulthood. Affected individuals may develop mild cognitive impairment and hearing loss caused by abnormalities of the inner ear (sensorineural hearing loss). They may experience weakness and loss of sensation due to problems with the nerves connecting the brain and spinal cord to muscles and sensory cells (peripheral nervous system). Clusters of enlarged blood vessels that form small, dark red spots on the skin (angiokeratomas) are characteristic of this form of the disorder.  https://medlineplus.gov/genetics/condition/schindler-disease

Clinical features

From HPO
Aminoaciduria
MedGen UID:
116067
Concept ID:
C0238621
Disease or Syndrome
An increased concentration of an amino acid in the urine.
Increased urinary O-linked sialopeptides
MedGen UID:
373111
Concept ID:
C1836533
Finding
Excretion of peptides conjugated to sialic acid in the urine.
Sensorineural hearing loss disorder
MedGen UID:
9164
Concept ID:
C0018784
Disease or Syndrome
A type of hearing impairment in one or both ears related to an abnormal functionality of the cochlear nerve.
Vertigo
MedGen UID:
53006
Concept ID:
C0042571
Sign or Symptom
An abnormal sensation of spinning while the body is actually stationary.
Intellectual disability, mild
MedGen UID:
10044
Concept ID:
C0026106
Mental or Behavioral Dysfunction
Mild intellectual disability is defined as an intelligence quotient (IQ) in the range of 50-69.
Cerebral atrophy
MedGen UID:
116012
Concept ID:
C0235946
Disease or Syndrome
Atrophy (wasting, decrease in size of cells or tissue) affecting the cerebrum.
Cognitive impairment
MedGen UID:
90932
Concept ID:
C0338656
Mental or Behavioral Dysfunction
Abnormal cognition is characterized by deficits in thinking, reasoning, or remembering.
Peripheral axonal neuropathy
MedGen UID:
266071
Concept ID:
C1263857
Disease or Syndrome
An abnormality characterized by disruption of the normal functioning of peripheral axons.
White mater abnormalities in the posterior periventricular region
MedGen UID:
373109
Concept ID:
C1836525
Finding
Distal sensory impairment of all modalities
MedGen UID:
322937
Concept ID:
C1836527
Finding
Reduced ability to sense pain, temperature, touch, vibration stimuli in the distal regions of the extremities.
Axonal degeneration
MedGen UID:
332464
Concept ID:
C1837496
Finding
Distal sensory impairment
MedGen UID:
335722
Concept ID:
C1847584
Finding
An abnormal reduction in sensation in the distal portions of the extremities.
Lacunar stroke
MedGen UID:
465269
Concept ID:
C3178801
Disease or Syndrome
A stroke related to a small infarct (2-20 mm in diameter) in the deep cerebral white matter, basal ganglia, or pons, that is presumed to result from the occlusion of a single small perforating artery supplying the subcortical areas of the brain.
Distal muscle weakness
MedGen UID:
140883
Concept ID:
C0427065
Finding
Reduced strength of the musculature of the distal extremities.
Lymphedema
MedGen UID:
6155
Concept ID:
C0024236
Disease or Syndrome
Localized fluid retention and tissue swelling caused by a compromised lymphatic system.
Depressed nasal bridge
MedGen UID:
373112
Concept ID:
C1836542
Finding
Posterior positioning of the nasal root in relation to the overall facial profile for age.
Thick lower lip vermilion
MedGen UID:
326567
Concept ID:
C1839739
Finding
Increased thickness of the lower lip, leading to a prominent appearance of the lower lip. The height of the vermilion of the lower lip in the midline is more than 2 SD above the mean. Alternatively, an apparently increased height of the vermilion of the lower lip in the frontal view (subjective).
Coarse facial features
MedGen UID:
335284
Concept ID:
C1845847
Finding
Absence of fine and sharp appearance of brows, nose, lips, mouth, and chin, usually because of rounded and heavy features or thickened skin with or without thickening of subcutaneous and bony tissues.
Fabry disease
MedGen UID:
8083
Concept ID:
C0002986
Disease or Syndrome
Fabry disease is the most common of the lysosomal storage disorders and results from deficient activity of the enzyme alpha-galactosidase A (a-Gal A), leading to progressive lysosomal deposition of globotriaosylceramide and its derivatives in cells throughout the body. The classic form, occurring in males with less than 1% a-Gal A enzyme activity, usually has its onset in childhood or adolescence with periodic crises of severe pain in the extremities (acroparesthesia), the appearance of vascular cutaneous lesions (angiokeratomas), sweating abnormalities (anhidrosis, hypohidrosis, and rarely hyperhidrosis), characteristic corneal and lenticular opacities, and proteinuria. Gradual deterioration of renal function to end-stage renal disease (ESRD) usually occurs in men in the third to fifth decade. In middle age, most males successfully treated for ESRD develop cardiac and/or cerebrovascular disease, a major cause of morbidity and mortality. Heterozygous females typically have milder symptoms at a later age of onset than males. Rarely, females may be relatively asymptomatic throughout a normal life span or may have symptoms as severe as those observed in males with the classic phenotype. In contrast, late-onset forms occur in males with greater than 1% a-Gal A activity. Clinical manifestations include cardiac disease, which usually presents in the sixth to eighth decade with left ventricular hypertrophy, cardiomyopathy, arrhythmia, and proteinuria; renal failure, associated with ESRD but without the skin lesions or pain; or cerebrovascular disease presenting as stroke or transient ischemic attack.
Petechiae
MedGen UID:
10680
Concept ID:
C0031256
Disease or Syndrome
Petechiae are pinpoint-sized reddish/purple spots, resembling a rash, that appear just under the skin or a mucous membrane when capillaries have ruptured and some superficial bleeding into the skin has happened. This term refers to an abnormally increased susceptibility to developing petechiae.
Dry skin
MedGen UID:
56250
Concept ID:
C0151908
Sign or Symptom
Skin characterized by the lack of natural or normal moisture.
Hyperkeratosis
MedGen UID:
209030
Concept ID:
C0870082
Disease or Syndrome
Hyperkeratosis is thickening of the outer layer of the skin, the stratum corneum, which is composed of large, polyhedral, plate-like envelopes filled with keratin which are the dead cells that have migrated up from the stratum granulosum.
Lip telangiectasia
MedGen UID:
347522
Concept ID:
C1857697
Finding
Telangiectasia (that is, the presence of small dilated superficial blood vessels) of the lips.
Telangiectasia of the oral mucosa
MedGen UID:
870436
Concept ID:
C4024882
Anatomical Abnormality
Telangiectasia (that is, the presence of small dilated superficial blood vessels) of the oral mucosa.
Tortuosity of conjunctival vessels
MedGen UID:
344487
Concept ID:
C1855391
Finding
The presence of an increased number of twists and turns of the conjunctival blood vessels.

Term Hierarchy

CClinical test,  RResearch test,  OOMIM,  GGeneReviews,  VClinVar  
  • CROGVAlpha-N-acetylgalactosaminidase deficiency type 2
Follow this link to review classifications for Alpha-N-acetylgalactosaminidase deficiency type 2 in Orphanet.

Recent clinical studies

Diagnosis

Mohamed FE, Al Sorkhy M, Ghattas MA, Al-Zaabi N, Al-Shamsi A, Almansoori TM, Al-Gazali L, Al-Dirbashi OY, Al-Jasmi F, Ali BR
J Mol Neurosci 2020 Jan;70(1):45-55. Epub 2019 Aug 29 doi: 10.1007/s12031-019-01398-6. PMID: 31468281
Sarbu M, Zhu F, Peter-Katalinić J, Clemmer DE, Zamfir AD
Rapid Commun Mass Spectrom 2015 Nov 15;29(21):1929-37. doi: 10.1002/rcm.7288. PMID: 26443390
Sarbu M, Robu A, Peter-Katalinić J, Zamfir AD
Carbohydr Res 2014 Oct 29;398:90-100. Epub 2014 Sep 6 doi: 10.1016/j.carres.2014.08.014. PMID: 25243357
Casado M, Altimira L, Montero R, Castejón E, Nascimento A, Pérez-Dueñas B, Ormazabal A, Artuch R
Anal Bioanal Chem 2014 Jul;406(18):4337-43. Epub 2014 May 2 doi: 10.1007/s00216-014-7832-6. PMID: 24788891

Clinical prediction guides

Casado M, Altimira L, Montero R, Castejón E, Nascimento A, Pérez-Dueñas B, Ormazabal A, Artuch R
Anal Bioanal Chem 2014 Jul;406(18):4337-43. Epub 2014 May 2 doi: 10.1007/s00216-014-7832-6. PMID: 24788891

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