Differential Diagnosis
Amish Lethal Microcephaly Microcephaly has a wide variety of causative factors. It can be syndromic or isolated, environmental or genetic, congenital or acquired . Metabolic testing (including urine organic acids, plasma amino acids, lactate, pyruvate, and electrolytes) is indicated for all children with congenital microcephaly. Further specific evaluations are performed as indicated based on the results of this testing. The primary microcephalies are a group of rare, phenotypically and etiologically heterogeneous disorders of brain growth characterized by (1) a head circumference two or more standard deviations (SD) below the mean at birth and three or more SD below the mean by age one year, and (2) mild-to-severe intellectual disability. Additional clinical or neuroimaging features can be associated. Most primary microcephalies are inherited in an autosomal recessive manner. To date, pathogenic variants in more than 100 genes are known to cause primary microcephaly (for review, see ). (See also WDR62 Primary Microcephaly and ASPM Primary Microcephaly.) The degree of microcephaly is much greater in Amish lethal microcephaly than in any of these other genetically defined microcephaly syndromes. Additionally, 2-ketoglutaric aciduria is a good clue for the diagnosis of Amish lethal microcephaly, as 2-ketoglutaric aciduria has not been reported as a finding in other genetically defined microcephaly syndromes. Alpha-ketoglutarate. Among other genetic malformation syndromes, a similar level of urinary 2-ketoglutarate is also characteristic of DOORS (deafness, onychodystrophy, osteodystrophy, intellectual disability [formerly known as mental retardation], seizures) syndrome, caused by biallelic pathogenic variants in TBC1D24. Microcephaly is noted in one third of individuals with DOORS syndrome. (See TBC1D24-Related Disorders.) Thiamine Metabolism Dysfunction Syndrome 4 Table 2. Genes of Interest in the Differential Diagnosis of Thiamine Metabolism Dysfunction Syndrome 4
Gene | Disorder | MOI | Clinical Characteristics/ Comment |
|---|
Primary mitochondrial disorders | ARADXLMat | levels of urinary 2-ketoglutarate are common in wide variety of disorders of mitochondrial dysfunction, incl those caused by mutation of both mtDNA nuclear DNA genes. | — |
BCKDHABCKDHBDBTIVDMCEEMMAAMMABMMADHCMMUTPCCAPCCB2 | Organic acid disorders (e.g., isolated methylmalonic acidemia, maple syrup urine disease, propionic acidemia) | AR | Major clinical features are developmental delay, seizures, lethargy, coma, hypotonia, vomiting, poor weight gain, growth deficiency, hepatomegaly, respiratory distress, cardiac dysfunction, hypoglycemia, acidosis. DLD |
Dihydrolipoamide dehydrogenase deficiency | AR | levels of urinary alpha-ketoglutarate may be seen in persons w/pathogenic variants in the alpha-ketoglutarate dehydrogenase complex. | — |
NUP62 | Infantile striatonigral degeneration (OMIM 271930) | ... | — |
Source: GeneReviews — "SLC25A19-Related Thiamine Metabolism Dysfunction"
