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Alpha-N-acetylgalactosaminidase deficiency type 1

MedGen UID:
373113
Concept ID:
C1836544
Disease or Syndrome
Synonyms: ALPHA-N-ACETYLGALACTOSAMINIDASE DEFICIENCY, TYPE I; NAGA deficiency, type 1; NAGA DEFICIENCY, TYPE I; Neuroaxonal dystrophy, Schindler type; Schindler Disease; Schindler disease, type 1; SCHINDLER DISEASE, TYPE I
SNOMED CT: Schindler disease (238048001); Alpha-N-acetylgalactosaminidase deficiency (238048001); Schindler disease type 1 (879937000); Alpha-N-acetylgalactosaminidase deficiency type 1 (879937000); NAGA (alpha-N-acetylgalactosaminidase) deficiency (238048001); NAGA (alpha-N-acetylgalactosaminidase) deficiency type 1 (879937000)
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:0012221
OMIM®: 609241
Orphanet: ORPHA79279

Definition

Alpha-N-acetylgalactosaminidase (NAGA) deficiency is a very rare lysosomal storage disorder. It is clinically heterogeneous with 3 main phenotypes: type I is an infantile-onset neuroaxonal dystrophy; type II, also known as Kanzaki disease (609242), is an adult-onset disorder characterized by angiokeratoma corporis diffusum and mild intellectual impairment; and type III is an intermediate disorder with mild to moderate neurologic manifestations (Desnick and Schindler, 2001). [from OMIM]

Additional description

From MedlinePlus Genetics
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.

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.

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 is an inherited disorder that primarily causes neurological problems.  https://medlineplus.gov/genetics/condition/schindler-disease

Clinical features

From HPO
Increased urinary O-linked sialopeptides
MedGen UID:
373111
Concept ID:
C1836533
Finding
Excretion of peptides conjugated to sialic acid in the urine.
Spasticity
MedGen UID:
7753
Concept ID:
C0026838
Sign or Symptom
A motor disorder characterized by a velocity-dependent increase in tonic stretch reflexes with increased muscle tone, exaggerated (hyperexcitable) tendon reflexes.
Myoclonus
MedGen UID:
10234
Concept ID:
C0027066
Finding
Very brief, involuntary random muscular contractions occurring at rest, in response to sensory stimuli, or accompanying voluntary movements.
Seizure
MedGen UID:
20693
Concept ID:
C0036572
Sign or Symptom
A seizure is an intermittent abnormality of nervous system physiology characterised by a transient occurrence of signs and/or symptoms due to abnormal excessive or synchronous neuronal activity in the brain.
Intellectual disability, severe
MedGen UID:
48638
Concept ID:
C0036857
Mental or Behavioral Dysfunction
Severe mental retardation is defined as an intelligence quotient (IQ) in the range of 20-34.
Hyperreflexia
MedGen UID:
57738
Concept ID:
C0151889
Finding
Hyperreflexia is the presence of hyperactive stretch reflexes of the muscles.
Global developmental delay
MedGen UID:
107838
Concept ID:
C0557874
Finding
A delay in the achievement of motor or mental milestones in the domains of development of a child, including motor skills, speech and language, cognitive skills, and social and emotional skills. This term should only be used to describe children younger than five years of age.
Developmental regression
MedGen UID:
324613
Concept ID:
C1836830
Disease or Syndrome
Loss of developmental skills, as manifested by loss of developmental milestones.
Hypotonia
MedGen UID:
10133
Concept ID:
C0026827
Finding
Hypotonia is an abnormally low muscle tone (the amount of tension or resistance to movement in a muscle). Even when relaxed, muscles have a continuous and passive partial contraction which provides some resistance to passive stretching. Hypotonia thus manifests as diminished resistance to passive stretching. Hypotonia is not the same as muscle weakness, although the two conditions can co-exist.
Osteopenia
MedGen UID:
18222
Concept ID:
C0029453
Disease or Syndrome
Osteopenia is a term to define bone density that is not normal but also not as low as osteoporosis. By definition from the World Health Organization osteopenia is defined by bone densitometry as a T score -1 to -2.5.
Generalized amyotrophy
MedGen UID:
234650
Concept ID:
C1389113
Disease or Syndrome
Generalized (diffuse, unlocalized) amyotrophy (muscle atrophy) affecting multiple muscles.
Generalized hypotonia
MedGen UID:
346841
Concept ID:
C1858120
Finding
Generalized muscular hypotonia (abnormally low muscle tone).
Reduced alpha-N-acetylgalactosaminidase activity in cultured fibroblasts
MedGen UID:
1050855
Concept ID:
CN375673
Finding
Concentration or activity of alpha-N-acetylgalactosaminidase (EC 3.2.1.49) as measured in cultured fibroblasts is below the limits of normal.
Nystagmus
MedGen UID:
45166
Concept ID:
C0028738
Disease or Syndrome
Rhythmic, involuntary oscillations of one or both eyes related to abnormality in fixation, conjugate gaze, or vestibular mechanisms.
Optic atrophy
MedGen UID:
18180
Concept ID:
C0029124
Disease or Syndrome
Atrophy of the optic nerve. Optic atrophy results from the death of the retinal ganglion cell axons that comprise the optic nerve and manifesting as a pale optic nerve on fundoscopy.
Strabismus
MedGen UID:
21337
Concept ID:
C0038379
Disease or Syndrome
A misalignment of the eyes so that the visual axes deviate from bifoveal fixation. The classification of strabismus may be based on a number of features including the relative position of the eyes, whether the deviation is latent or manifest, intermittent or constant, concomitant or otherwise and according to the age of onset and the relevance of any associated refractive error.
Cerebral visual impairment
MedGen UID:
890568
Concept ID:
C4048268
Pathologic Function
A form of loss of vision caused by damage to the visual cortex rather than a defect in the eye.

Term Hierarchy

CClinical test,  RResearch test,  OOMIM,  GGeneReviews,  VClinVar  
  • CROGVAlpha-N-acetylgalactosaminidase deficiency type 1

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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