Table 3.

Disorders to Consider in the Differential Diagnosis of CLPB Deficiency

Discriminating FeatureGene(s)DisorderMOIAdditional Hallmarks 1 of Disorder
3-MGA-uria 2 AGK AGK defect (Sengers syndrome) (See DNA mtDNA Maintenance Defects Overview.)ARCharacteristic combination of bilateral cataracts, hypertrophic cardiomyopathy, & no to mild ID. Can be lethal in neonatal period but survivors to adulthood w/mild involvement are known.
AUH AUH defect (3-methylglutaconyl-CoA hydratase deficiency) (OMIM 250950)ARAdult-onset progressive spasticity & dementia w/characteristic slowly developing radiologic picture of extensive leukoencephalopathy 3. Uniquely distinguished by ↑ urinary excretion of 3-HIVA.
DNAJC19 DNAJC19 defect (DCMA syndrome) (OMIM 610198)ARCharacteristic combination of childhood-onset dilated cardiomyopathy, non-progressive cerebellar ataxia, testicular dysgenesis, growth failure
OPA3 OPA3 defect (See Costeff Syndrome.)ARIn infants: optic atrophy & movement disorder (ataxia or extrapyramidal disorder)
SERAC1 MEGD(H)EL syndrome (See SERAC1 Deficiency.)ARNeonatal hypoglycemia & liver failure 4. In 2nd yr of life: progressive SNHL & neurologic manifestations (truncal hypotonia, spasticity of limbs, dystonia, severe ID/DD, Leigh syndrome-like findings on MRI).
TAFAZZIN (formerly TAZ)TAZ defect (See Barth syndrome.)XLIn affected males: growth delay in infancy, cardiomyopathy (left ventricular noncompaction), neutropenia, myopathy, typical facial features, hypocholesterolemia, & cognitive phenotype
TMEM70 TMEM70 defect (OMIM 614052)ARNo specific syndromic presentation to date. Typically in neonates: hyperammonemia, lactic acidosis, muscular hypotonia, hypertrophic cardiomyopathy, psychomotor retardation. In those surviving neonatal period: DD.
UnknownNot otherwise specified 3-MGA-uria (former 3-MGCA 4)Normal 3-methylglutaconyl-CoA hydratase enzyme activity & no defect in TAFAZZIN, OPA3, SERAC1, TMEM70, DNAJC5, AUH, or AGK
Congenital neutropenia & cyclic neutropenia ELANE ELANE-related neutropenia ADIsolated neutropenia; no involvement of CNS or other organs
G6PC3 G6PC3 deficiency ARPresence of cardiovascular &/or urogenital abnormalities
GATA1 GATA1-related X-linked cytopenia XLTypical presentation in affected males: bleeding disorder & anemia; neutropenia occurs later
DNAJC21
EFL1
SBDS
SRP54 		Shwachman-Diamond syndrome AR

AD 5

Intestinal malabsorption due to exocrine pancreatic dysfunction
WAS X-linked severe congenital neutropenia (See WAS-Related Disorders.)XLIsolated neutropenia; no involvement of CNS or other organs
Hyperekplexia ARHGEF9 Early-infantile epileptic encephalopathy 8 (OMIM 300607)XL
GLRA1
GLRB
SLC6A5 		Hereditary hyperekplexia AD
AR 6		Generalized stiffness immediately after birth normalizes in 1st yrs of life. Unexpected (esp auditory) stimuli cause excessive startle reflex (eye blinking, flexor spasm of the trunk), followed by short period of generalized stiffness in which voluntary movements are impossible. Neutropenia/severe infections, respiratory insufficiency, & swallowing problems are not seen in neonates; affected persons improve over time.
GPHN Molybdenum cofactor deficiency, complementation group C (See Molybdenum Cofactor Deficiency.)AR

3-HIVA = 3-hydroxyisovaleric acid; 3-MGA = 3-methylglutaconic acid; AD = autosomal dominant; AR = autosomal recessive; CNS = central nervous system; DD = developmental delay; ID = intellectual disability; MOI = mode of inheritance; mtDNA = mitochondrial DNA; SNHL = sensorineural hearing loss; XL = X-linked

1.

In addition to discriminative feature shown in column 1

2.

Increased urinary excretion of 3-MGA, known as 3-methylglutaconic aciduria (3-MGA-uria), is a relatively common finding in children investigated for suspected inborn errors of metabolism [Wortmann et al 2013]. Click here (pdf) for information on classification of inborn errors of metabolism in which 3-methylglutaconic aciduria is a discriminative feature.

3.
4.
5.

Shwachman-Diamond syndrome (SDS) caused by pathogenic variants in DNAJC21, EFL1, or SBDS is inherited in an autosomal recessive manner. SDS caused by pathogenic variants in SRP54 is inherited in an autosomal dominant manner.

6.

Hereditary hyperekplexia caused by pathogenic variants in GLRA1 or GLRB is inherited in an autosomal recessive or (less commonly) an autosomal dominant manner. Hereditary hyperekplexia caused by pathogenic variants in SLC6A5 is usually inherited in an AR manner (AD inheritance reported in 1 family).

From: CLPB Deficiency

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