Table 4.

Genes of Interest in the Differential Diagnosis of SERAC1 Deficiency

GeneDisorderMOIFeatures of Differential Diagnosis Disorder
3-MGA-uriaKey clinical characteristics
ACTB ACTB Baraitser-Winter cerebrofrontofacial syndrome w/juvenile-onset dystoniaADAbsentDeafness, dystonia, ID, DD
AGK Sengers syndrome (See Mitochondrial DNA Maintenance Defects Overview.)ARPresent *Cataracts, cardiomyopathy, (DD 1)
ATAD3A Harel-Yoon syndrome (OMIM 617183)AD
AR		Present *Global DD, hypotonia, optic atrophy, axonal neuropathy, hypertrophic cardiomyopathy 2
AUH AUH defect (OMIM 250950)ARPresent *Adult-onset progressive spasticity & dementia w/characteristic slowly developing radiologic picture of extensive leukoencephalopathy 3, 4
BCAP31 Deafness, dystonia, & cerebral hypomyelination (OMIM 300475)XLAbsentDeafness, dystonia, ID, DD, cerebral hypomyelination
CLPB CLPB deficiency ARPresent *Cataracts, central hypopnea, DD, ID, movement disorder, neutropenia, (epilepsy 1)
DNAJC19 DNAJC19 defect (DCMA syndrome) (OMIM 610198)ARPresent *Characteristic combination of childhood-onset dilated cardiomyopathy, nonprogressive cerebellar ataxia, testicular dysgenesis, & growth failure
FITM2 Siddiqi syndrome (OMIM 618635)ARAbsentDeafness, dystonia, ID, DD
HTRA2 MGCA8 (OMIM 617248)ARPresent *Cataracts, central hypopnea, DD, ID, epilepsy, movement disorder, neutropenia
MICOS13
(C19orf70,
QIL1)		Combined oxidative phosphorylation deficiency 37 (OMIM 618329)ARPresent *Hypotonia, failure to thrive, neurodegeneration w/loss of developmental milestones, liver dysfunction
OPA3 Costeff syndrome ARPresent *Optic atrophy, movement disorder (ataxia or extrapyramidal disorder)
SUCLA2 SUCLA2 mtDNA depletion syndrome, encephalomyopathic form w/methylmalonic aciduria ARMay be present
  • Early-onset dystonia, deafness, severe failure to thrive
  • Basal ganglia involvement visible on brain MRI in some
  • Movement disorder, epilepsy, 3-MGA-uria, & ↑ serum lactate common.
  • Characteristic metabolite profile: mild ↑ in urinary methylmalonic acid & serum acyl-carnitine ester abnormalities 5 (metabolite profile not found in MEGD[H]EL syndrome)
TAFAZZIN (TAZ) Barth syndrome XLPresent *In males, cardiomyopathy (left ventricular noncompaction), neutropenia, myopathy, typical facial features, hypocholesterolemia, & cognitive phenotype
TIMM50 MGCA9 (OMIM 617698)ARPresent *DD, ID, epilepsy
TIMM8A Deafness-dystonia-optic neuronopathy syndrome XLAbsent 6
  • Progressive deafness in infancy
  • Dystonia develops later in life; may develop in adulthood.
  • Basal ganglia lesions can be found on brain MRI.
TMEM70 TMEM70 defect (OMIM 614052)ARPresent *
  • Typically neonatal onset w/muscular hypotonia, hypertrophic cardiomyopathy, psychomotor disability, hyperammonemia, & lactic acidosis
  • Children surviving neonatal period later show DD.
  • Phenotypic spectrum is variable. 7

3-MGA-uria = 3-methylglutaconic aciduria; DD = developmental delay; ID = intellectual disability; MOI = mode of inheritance; XL = X-linked

See also Kovacs-Nagy et al [2018], Table 1.

* 3-MGA-uria is a discriminative feature of this disorder.

1.

Seen in some affected persons

2.
3.
4.

AUH defect is the only one of the five inborn errors of metabolism with 3-MGA-uria with a distinct biochemical finding: elevated urinary excretion of 3-hydroxyisovaleric acid (3-HIVA).

5.

Increased C3- & C4-dicarboxyli-carnitine esters.

6.
7.

The phenotypic spectrum of TMEM70 defect is variable and becoming broader as more affected individuals are reported. At this time no specific syndromic presentation is evident.

From: SERAC1 Deficiency

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