Table 2.

Other Genes of Interest in the Differential Diagnosis of DDON Syndrome

Gene(s) 1Differential
Disorder		MOIFeatures of Differential Disorder
Overlapping w/DDON syndromeDistinguishing from DDON syndrome
MT-TL1 2 MELAS Mat
  • Dystonia uncommon in MELAS
  • Short stature, generalized tonic-clonic seizures, recurrent headaches/vomiting, & anorexia common in MELAS
SERAC1 MEGDEL syndrome ARDystonia & deafnessLeigh-like features, impaired oxidative phosphorylation, & 3-methylglutaconic aciduria
SUCLA2 SUCLA2-related mtDNA depletion syndrome, encephalomyopathic form w/methylmalonic aciduria 3AR
  • Progressive disorder
  • Dystonia & severe hearing impairment
  • Hypotonia, abnormal muscle histopathology, & ↑ methylmalonic acid concentration
  • Ophthalmologic findings normal
  • Several cases reported from Faroe Islands
PRPS1 Arts syndrome (See Phosphoribosylpyrophosphate Synthetase Deficiency.) 4XLIntellectual impairment, ataxia, & hearing impairmentArts syndrome findings range from isolated hearing impairment to hearing impairment assoc w/optic atrophy, hypotonia, ataxia, ID, & signs of peripheral neuropathy, but not dystonia.
XK McLeod neuroacanthocytosis syndrome XLMovement disorder, cognitive impairment, & psychiatric symptoms in males
  • Neurodegenerative basal ganglia disease
  • Neuromuscular manifestations incl (mostly subclinical) sensorimotor axonopathy & clinically relevant muscle weakness or atrophy
  • Hematologic manifestations: RBC acanthocytosis, compensated hemolysis, & McLeod blood group phenotype
  • Dilated cardiomyopathy & arrhythmias
CDH23
CIB2
MYO7A
PCDH15
USH1C
USH1G
USH1H 5		 Usher syndrome type I AR
  • Visual & hearing impairment
  • In persons w/DDON, Usher may first be suspected because hearing impairment in DDON may be congenital & in Usher type II may be progressive.
  • Impaired vision results from retinal dystrophy, which first manifests as impaired dark adaptation 6 (vs DDON, where appearance of retina is usually normal, as are night vision & ERG).
  • No neurologic abnormalities
ADGRV1
USH2A
WHRN 5		 Usher syndrome type II AR
WFS1 Wolfram syndrome AR
  • Optic atrophy, movement disorder, dementia, & psychiatric abnormalities may occur.
  • Hearing impairment in ~60% of persons by age 20 yrs
  • Consider Wolfram in simplex males (i.e., single case in a family) who appear to have DDON.
  • Juvenile onset of diabetes mellitus
  • Involvement of most organs
  • No dystonia
FXN Friedreich ataxia AR
  • Slowly progressive ataxia w/onset age usually <25 yrs
  • May be assoc w/sensorineural hearing impairment (10% of persons) & often subclinical optic atrophy (25%)
  • Rarely presents w/hearing impairment or optic atrophy (hearing loss is always a presenting finding in DDON)
  • Dystonia & other movement disorders uncommon
  • Tendon reflexes usually (not always) depressed in Friedreich ataxia
  • Cardiomyopathy common

AR = autosomal recessive; CNS = central nervous system; ERG = electroretinogram; ID = intellectual disability; Mat = maternal; MELAS = mitochondrial encephalomyopathy, lactic acidosis, and strokelike episodes; MOI = mode of inheritance; mt = mitochondrial; RBC = red blood cell; XL = X-linked

1.

Genes are in alphabetic order.

2.

The m.3243A>G pathogenic variant in the mitochondrial gene MT-TL1 is present in approximately 80% of individuals with MELAS. Pathogenic variants in MT-TL1nor other mtDNA genes, particularly MT-ND5, can also cause this disorder.

3.

The disorder was identified in a Muslim family and ten remotely related individuals from the Faroe Islands, where a high carrier frequency (1 in 33) is caused by a founder variant [Ostergaard et al 2007].

4.

See also other heredodegenerative X-linked disorders characterized by intellectual impairment, movement disorder, and hearing impairment, including Farlow syndrome (OMIM 301840), Schimke syndrome (OMIM 312840), Wells syndrome (OMIM 312910), and Schmidley syndrome (OMIM 301790).

5.

See Phenotypic Series: Usher syndrome for additional genes associated with this phenotype in OMIM.

6.

Ophthalmoscopy and electroretinography can be used to determine the cause of visual impairment.

From: Deafness-Dystonia-Optic Neuronopathy Syndrome

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