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Juvenile-onset diabetes mellitus-central and peripheral neurodegeneration syndrome(ACPHD)

MedGen UID:
863873
Concept ID:
C4015436
Disease or Syndrome
Synonym: Ataxia, combined cerebellar and peripheral, with hearing loss and diabetes mellitus
SNOMED CT: Juvenile-onset diabetes mellitus, central and peripheral neurodegeneration syndrome (1255271005); Combined cerebellar and peripheral ataxia, deafness, diabetes mellitus syndrome (1255271005); Combined cerebellar and peripheral ataxia, hearing loss, diabetes mellitus syndrome (1255271005)
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): DNAJC3 (13q32.1)
 
Monarch Initiative: MONDO:0014523
OMIM®: 616192
Orphanet: ORPHA445062

Definition

Combined cerebellar and peripheral ataxia with hearing loss and diabetes mellitus (ACPHD) is an autosomal recessive multisystem disorder including defects in glucose metabolism, diffuse neurodegeneration, multiple hormone deficiencies, severe growth retardation with possible growth hormone deficiencies, and subtle osseous changes suggesting early-onset bone dysplasia (summary by Ozon et al., 2020). [from OMIM]

Clinical features

From HPO
Areflexia of lower limbs
MedGen UID:
347285
Concept ID:
C1856694
Finding
Inability to elicit tendon reflexes in the lower limbs.
Short stature
MedGen UID:
87607
Concept ID:
C0349588
Finding
A height below that which is expected according to age and gender norms. Although there is no universally accepted definition of short stature, many refer to "short stature" as height more than 2 standard deviations below the mean for age and gender (or below the 3rd percentile for age and gender dependent norms).
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.
Peripheral neuropathy
MedGen UID:
18386
Concept ID:
C0031117
Disease or Syndrome
Peripheral neuropathy is a general term for any disorder of the peripheral nervous system. The main clinical features used to classify peripheral neuropathy are distribution, type (mainly demyelinating versus mainly axonal), duration, and course.
Babinski sign
MedGen UID:
19708
Concept ID:
C0034935
Finding
Upturning of the big toe (and sometimes fanning of the other toes) in response to stimulation of the sole of the foot. If the Babinski sign is present it can indicate damage to the corticospinal tract.
Cerebral atrophy
MedGen UID:
116012
Concept ID:
C0235946
Disease or Syndrome
Atrophy (wasting, decrease in size of cells or tissue) affecting the cerebrum.
Sensory ataxia
MedGen UID:
66020
Concept ID:
C0240991
Sign or Symptom
Incoordination of movement caused by a deficit in the sensory nervous system. Sensory ataxia can be distinguished from cerebellar ataxia by asking the patient to close his or her eyes. Persons with cerebellar ataxia show only a minimal worsening of symptoms, whereas persons with sensory ataxia show a marked worsening of symptoms.
Cognitive impairment
MedGen UID:
90932
Concept ID:
C0338656
Mental or Behavioral Dysfunction
Abnormal cognition is characterized by deficits in thinking, reasoning, or remembering.
Cerebellar atrophy
MedGen UID:
196624
Concept ID:
C0740279
Disease or Syndrome
Cerebellar atrophy is defined as a cerebellum with initially normal structures, in a posterior fossa with normal size, which displays enlarged fissures (interfolial spaces) in comparison to the foliae secondary to loss of tissue. Cerebellar atrophy implies irreversible loss of tissue and result from an ongoing progressive disease until a final stage is reached or a single injury, e.g. an intoxication or infectious event.
Gait ataxia
MedGen UID:
155642
Concept ID:
C0751837
Sign or Symptom
A type of ataxia characterized by the impairment of the ability to coordinate the movements required for normal walking. Gait ataxia is characteirzed by a wide-based staggering gait with a tendency to fall.
Decreased sensory nerve conduction velocity
MedGen UID:
336512
Concept ID:
C1849148
Finding
Reduced speed of conduction of the action potential along a sensory nerve.
Decreased motor nerve conduction velocity
MedGen UID:
388130
Concept ID:
C1858729
Finding
A type of decreased nerve conduction velocity that affects the motor neuron.
Atrophy/Degeneration affecting the brainstem
MedGen UID:
870454
Concept ID:
C4024900
Disease or Syndrome
Elevated hemoglobin A1c
MedGen UID:
892798
Concept ID:
C4073162
Finding
An increased concentration of hemoglobin A1c (HbA1c), which is the product of nonenzymatic attachment of a hexose molecule to the N-terminal amino acid of the hemoglobin molecule. This reaction is dependent on blood glucose concentration, and therefore reflects the mean glucose concentration over the previous 8 to 12 weeks. The HbA1c level provides a better indication of long-term glycemic control than one-time blood or urinary glucose measurements.
Anti-islet antigen-2 antibody positivity
MedGen UID:
1813068
Concept ID:
C5575016
Finding
The presence of autoantibodies (immunoglobulins) in the serum that react against tyrosine phosphatase IA-2.
Diabetes mellitus type 1
MedGen UID:
41522
Concept ID:
C0011854
Disease or Syndrome
Type 1 diabetes mellitus (T1D), also designated insulin-dependent diabetes mellitus (IDDM), is a disorder of glucose homeostasis characterized by susceptibility to ketoacidosis in the absence of insulin therapy. It is a genetically heterogeneous autoimmune disease affecting about 0.3% of Caucasian populations (Todd, 1990). Genetic studies of T1D have focused on the identification of loci associated with increased susceptibility to this multifactorial phenotype. The classic phenotype of diabetes mellitus is polydipsia, polyphagia, and polyuria which result from hyperglycemia-induced osmotic diuresis and secondary thirst. These derangements result in long-term complications that affect the eyes, kidneys, nerves, and blood vessels.

Term Hierarchy

CClinical test,  RResearch test,  OOMIM,  GGeneReviews,  VClinVar  
  • CROGVJuvenile-onset diabetes mellitus-central and peripheral neurodegeneration syndrome
  • Hereditary ataxia
    • Juvenile-onset diabetes mellitus-central and peripheral neurodegeneration syndrome

Recent clinical studies

Therapy

Giannakopoulou C, Korakaki E, Hatzidaki E, Manoura A, Aligizakis A, Velivasakis E
Pediatrics 2002 Apr;109(4):e66. doi: 10.1542/peds.109.4.e66. PMID: 11927739

Prognosis

Watkins PJ, Gayle C, Alsanjari N, Scaravilli F, Zanone M, Thomas PK
QJM 1995 Nov;88(11):795-804. PMID: 8542264

Clinical prediction guides

Alfaro R, Nicanor-Carreón JG, Doty T, Lugar H, Hershey T, Pepino MY
Chem Senses 2023 Jan 1;48 doi: 10.1093/chemse/bjad004. PMID: 36798000Free PMC Article
Giannakopoulou C, Korakaki E, Hatzidaki E, Manoura A, Aligizakis A, Velivasakis E
Pediatrics 2002 Apr;109(4):e66. doi: 10.1542/peds.109.4.e66. PMID: 11927739
Rouanet-Larriviere M, Vital C, Arne P, Favarel-Garrigues JC, Gin H, Vital A
J Peripher Nerv Syst 2000 Mar;5(1):27-31. doi: 10.1046/j.1529-8027.2000.00122.x. PMID: 10780681
Watkins PJ, Gayle C, Alsanjari N, Scaravilli F, Zanone M, Thomas PK
QJM 1995 Nov;88(11):795-804. PMID: 8542264

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