MR Imaging Findings in the Reticular Formation in Siblings withMPV17-Related Mitochondrial Depletion Syndrome

Abstract

SUMMARY:Hepatocerebral MPV17-MDS is quite rare (Ͻ30 confirmed cases), with limited findings described on MR imaging. We report 2 siblings having abnormalities within the reticular formation of the lower brain stem and within the reticulospinal tracts at the cervicocranial junction on T2WI. The presence of these MR imaging findings (relative to previous reports) raises the possibility that they represent subtle but characteristic findings corresponding to clinically observed abnormalities of tone encountered with this recently described disorder. ABBREVIATIONS:1 H-MR spectroscopy ϭ proton MR spectroscopy; MDS ϭ mitochondrial depletion syndrome; MPV17-MDS ϭ MPV17-related mitochondrial depletion syndrome; T1WI ϭ T1-weighted imaging; T2WI ϭ T2-weighted imaging M PV17-related hepatocerebral MDS is a rare congenital autosomal recessive disorder typically characterized by hepatic failure, failure to thrive, and neurologic findings (dependent on the age of onset), such as hypotonia and dystonic movements.1,2 It is 1 of several described MDSs recently confirmed by dedicated laboratory and genetic testing.2 Presentation usually occurs in the first months of life, with the life span typically limited to months.1,2 The MR imaging literature describing MPV17-MDS is sparse and nonspecific, but the variable findings that have been reported range from normal-todiffuse white matter abnormalities, which may resemble a leukodystrophy or hypomyelination.1 Particular regions noted in case reports include the cerebellar white matter, middle cerebellar peduncles, substantia nigra, and a single patient with subtle involvement of the dorsal brain stem.2-4 Herein, we describe 2 infant siblings with MPV17-MDS exhibiting nearly identical involvement on T2WI at the cervicomedullary junction and within the lower dorsal brain stem. Case Reports Case 1A 3-month-old male infant with no significant perinatal/neonatal history presented with progressive deficiencies in feeding, jaundice, failure to thrive, and mild hypotonia; elevated liver enzymes were subsequently detected. Thereafter, a 1.5T MR imaging at 5 months of age demonstrated mild moderately delayed myelination, as represented on T1WI by limited hyperintensity within the anterior limb of the internal capsule, the corpus callosum splenium and lack of significant occipital white matter hyperintensity. There were hyperintense abnormalities on T2WI bilaterally within the reticular formation of the lower dorsal brain stem and the reticulospinal tracts of the cervicomedullary junction (Fig 1), without reduced diffusion. Findings of point-resolved 1 H-MR spectroscopy of the basal ganglia and periventricular white matter appeared normal for his age, without a lactate peak and with equivalent N-acetylaspartate and choline peaks. A head CT at 6.5 months of age did not demonstrate any significant abnormalities or overt atrophy. Hepatomegaly was clinically apparent and confirmed by CT. Muscle biopsies were performed but were negative for the more common mitochondrial disorders. The patient died at ...

Mitochondrial DNA Depletion Syndromes: Review and Updates of Genetic Basis, Manifestations, and Therapeutic Options

“…Approximately 30 affected individuals have been reported with MPV17-related hepatocerebral MDS [59][60][61][62][63][64][65][66][67][68]. Of note, among those confirmed cases are individuals with Navajo neurohepatopathy who were found to have homozygous p.Arg50Gln mutations in MPV17.…”

“…Less frequent manifestations include renal tubulopathy, hypoparathyroidism, and gastrointestinal dysmotility that manifests as gastroesophageal reflux, cyclic vomiting, and diarrhea. Corneal anesthesia and ulcers were reported in individuals homozygous for the mutation p.Arg50Gln [59][60][61][62][63][64][65][66][67][68].…”

Clinical, biochemical, cellular and molecular characterization of mitochondrial DNA depletion syndrome due to novel mutations in the MPV17 gene

“…3 To date, MDS caused by MPV17 mutations has been reported in 32 patients with the clinical manifestations including early progressive liver failure, neurological abnormalities, hypoglycaemia and raised blood lactate. 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 Recently, MPV17 mutations have also been associated with autosomal recessive adult-onset neuropathy and leukoencephalopathy with multiple mtDNA deletions in skeletal muscle. 16 Thus, as for POLG , RRM2B and TK2 , MPV17 mutations can lead to recessive MDS or recessive multiple mtDNA deletion disorders.…”

The role of the Mpv17 protein mutations of which cause mitochondrial DNA depletion syndrome (MDDS): lessons from homologs in different species

“…Besides hepatic and neurologic indications, hepatocerebral MDDS can result in metabolic manifestations, such as lactic acidosis and hypoglycemia, and it has frequently been observed that patients fail to thrive. Additional, less commonly noticed features are described in detail elsewhere (Karadimas et al, 2006;Spinazzola et al, 2006Spinazzola et al, , 2008Wong et al, 2007;NavarroSastre et al, 2008;Kaji et al, 2009;Parini et al, 2009;El-Hattab et al, 2010;Merkle et al, 2012;Uusimaa et al, 2013). Remarkably, the identical mutation might cause different severity, onset and pathology in different patients, as Blakely et al describe a patient with adult-onset of neuropathy and leukoencephalopathy, carrying a homozygous mutation (P98L) described in infantile MDDS syndrome previously (El-Hattab et al, 2010;Blakely et al, 2012).…”

“…Hepatic and neurologic manifestations appear to be the most characteristic findings. All early-onset patients studied presented with liver dysfunction, comprising cholestasis, jaundice and coagulopathy (see Karadimas et al, 2006;Spinazzola et al, 2006Spinazzola et al, , 2008Wong et al, 2007;Navarro-Sastre et al, 2008;Kaji et al, 2009;Parini et al, 2009;El-Hattab et al, 2010;Merkle et al, 2012;Uusimaa et al, 2013). Patients developing cirrhosis or hepatocellular carcinoma were described less frequently (see Karadimas et al, 2006;El-Hattab et al, 2010).…”