Table 1.

Clinical and genetic features of reported cases with RRM2M mutations

No	Reference number		Clinical features	CT/MRI of the brain	CK	Serum lactate	EMG	Skeletal muscle biopsies	Molecular genetic analysis
1	1	Family 1	Total of 3 subjects; a brother and two sisters, all with same clinical features: trunk hypotonia, proximal tubulopathy	NA	NA	++	NA	Severely decreased malate + glutamate oxidation and complex IV deficiency	Homozygous mutation (nt 850 C>T)
2
3
4		Family 2	Subject 1: trunk hypotonia, proximal tubulopathy, seizures	NA	NA	++	NA	Combined complex I, III, and IV deficiency	Compound heterozygote for a splice-site mutation (IVS3-2 A>G) and missense mutation (nt 580 G>A)
5			Subject 2: trunk hypotonia, proximal tubulopathy
6		Family 3	Subject 1: respiratory distress, hypotonia	NA	NA	++	NA	Few RRFs and lack of histochemical cytochrome c oxidase reaction in all fibers	Compound heterozygote for two missense mutations (nt 190 t > C, W64R, and nt 581 A>G,E194G)
7			Subject 2: Trunk hypotonia, vomiting, diarrhea	NA	NA	++	NA	RRFs, COX deficiency	3-bp inframe deletion (nt 253-255ΔGAG, ΔGlu85) and a missense mutation (nt 707 G>T, C236F)
8	2		Deafness, progressive weakness, poor head control, persistent diarrhea, respiratory distress	Spectroscopy showed the presence of lactate in the left basal ganglia†	normal	++	NA	RRFs with modified Gomori trichrome stain and ragged-blue fibers with the SDH stain. Lipid accumulation	Homozigous for a c.671 t > G mutation in exon 6
9			Failure to thrive, failure to gain developmental milestones, hypotonia, microcephaly, respiratory failure, urinary infections, intolerance to oral feeds, peripheral pigmentary retinopathy	Bilateral and nearly symmetrical non-enhancing areas of abnormal signal reduced diffusion in the white matter. Spectroscopy showed lactate peak in the basal ganglia and CSF‡	normal	+	NA	Scattered fibers with increased staining for SDH	Compound heterozygous for a missense mutation in exon 8 (c.846 G>C) and 1-bp deletion in exon 9 (c.920 delA)
10			Progressive hypotonia, failure to thrive and microcephaly, multiple respiratory infections	NA	+	+	NA	Scattered RRFs COX negative or COX deficient	Compound heterozygous for a missense mutation in exon 9 (c.949 t > G) and 1-bp deletion in exon 6 (c.584 delG)
11	3		Floppiness, congenital deafness, glycosuria	NA	+	++	Neurogenic lesion	RRFs COX negative, lipid accumulation	c.G122C p.R41P / c.G122C p.R41P
12			Floppiness, tubulopathy	NA	NA	++	NA	NA	IVS3-2A>C / c.C328T p.R110C
13	4	brothers	Feeding difficulties, failure to thrive, severe muscular hypotonia, seizures, proximal tubulopathy	NA	normal	++	NA	COX deficiency and accumulation of fat in muscle fibers	Missense mutation in exon 7 (c.686 G>T)
14			Feeding difficulties, failure to thrive, severe muscular hypotonia, seizures	Generalized atrophy‡	++	++	NA	COX deficiency and accumulation of fat in muscle fibers	Missense mutation in exon 7 (c.686 G>T)
15	Our case		Myopathy, deafness, peripheral neuropathy, nephrocalcinosis, proximal renal tubulopathy	Microlacunar hypodense zones in periventricular white matter of the frontal lobes, slightly dilated lateral ventricles and third ventricle, subarachnoid spaces in the Sylvian fissures moderately expanded†	normal	+	Neurogenic lesion of mild to moderate degree	Vacuolar myopathy, aggregation of mitochondria in some fibers. No RRFs	Missense mutation c.707 G>A, p.Cys236Tyr

*Abbreviations: CK – creatine phosphokinase; EMG – electromyography; RRF – ragged red fibers; COX – cyclooxygenase, SDH – succinate dehydrogenase; + – moderately elevated levels, ++ – significantly elevated levels, NA – data not reported.

†Computed tomography (CT) of the brain.

‡Magnetic resonance imaging (MRI) of the brain.