Anna Ardissone

Mitochondrial dysfunction in central nervous system white matter disorders

Defects of mitochondrial respiration and function had been proposed as a major culprit in the most common neurodegenerative diseases, including prototypic diseases of central nervous system (CNS) white matter such as multiple sclerosis. The importance of mitochondria for white matter is best exemplified in a group of defects of the mitochondria oxidative metabolism called mitochondria leukoencephalopathies or encephalomyopathies. These diseases are clinically and genetically heterogeneous, given the dual control of the respiratory chain by nuclear and mitochondrial DNA, which makes the precise diagnosis and classification challenging. Our understanding of disease pathogenesis is nowadays still limited. Here, we review current knowledge on pathogenesis and genetics, outlining diagnostic clues for the various forms of mitochondria disease. In particular, we underscore the value of magnetic resonance imaging (MRI) for the differential diagnosis of specific types of mitochondrial leukoencephalopathies, such as genetic defects on SDHFA1. The use of novel technologies for gene identification, such as whole‐exome sequencing studies, is expected to shed light on novel molecular etiologies, broadening prenatal diagnosis, disease understanding, and therapeutic options. Current treatments are mostly palliative, but very promising novel gene and pharmacologic therapies are emerging, which may also benefit a growing list of secondary mitochondriopathies, such as the peroxisomal disease adrenoleukodystrophy. GLIA 2014;62:1878–1894

Cavitating leukoencephalopathy with multiple mitochondrial dysfunction syndrome and NFU1 mutations

Multiple Mitochondrial Dysfunction Syndrome (MMDS) comprises a group of severe autosomal recessive diseases with onset in early infancy and characterized by a systemic disorder of energy metabolism, resulting in weakness, respiratory failure, lack of neurological development, lactic acidosis, and early death. Biochemical findings include defects of complexes I, II, and III of the mitochondrial respiratory chain and severe deficiency of Pyruvate dehydrogenase complex (PDHc). Three genes have been associated with MMDS since now: NFU1, BOLA3, and IBA57. We describe an Italian male patient presenting with severe psychomotor regression after an infectious episode, lactic acidosis, hyperglycinemia, reduction of respiratory chain complex II associated with a marked deficiency of PDHc activity. He carried two heterozygous mutations in NFU1, one novel (p.Cys210Phe) and one previously reported (p.Gly189Arg) missense change affecting highly conserved residues. A severe leukoencephalopathy with cavitations in deep white matter was disclosed at brain MRI, suggesting a peculiar neuroradiological phenotype associated with defect in this gene.

Mutations in APOPT1, encoding a mitochondrial protein, cause cavitating leukoencephalopathy with cytochrome c oxidase deficiency

Cytochrome c oxidase (COX) deficiency is a frequent biochemical abnormality in mitochondrial disorders, but a large fraction of cases remains genetically undetermined. Whole-exome sequencing led to the identification of APOPT1 mutations in two Italian sisters and in a third Turkish individual presenting severe COX deficiency. All three subjects presented a distinctive brain MRI pattern characterized by cavitating leukodystrophy, predominantly in the posterior region of the cerebral hemispheres. We then found APOPT1 mutations in three additional unrelated children, selected on the basis of these particular MRI features. All identified mutations predicted the synthesis of severely damaged protein variants. The clinical features of the six subjects varied widely from acute neurometabolic decompensation in late infancy to subtle neurological signs, which appeared in adolescence; all presented a chronic, long-surviving clinical course. We showed that APOPT1 is targeted to and localized within mitochondria by an N-terminal mitochondrial targeting sequence that is eventually cleaved off from the mature protein. We then showed that APOPT1 is virtually absent in fibroblasts cultured in standard conditions, but its levels increase by inhibiting the proteasome or after oxidative challenge. Mutant fibroblasts showed reduced amount of COX holocomplex and higher levels of reactive oxygen species, which both shifted toward control values by expressing a recombinant, wild-type APOPT1 cDNA. The shRNA-mediated knockdown of APOPT1 in myoblasts and fibroblasts caused dramatic decrease in cell viability. APOPT1 mutations are responsible for infantile or childhood-onset mitochondrial disease, hallmarked by the combination of profound COX deficiency with a distinctive neuroimaging presentation.

A slowly progressive mitochondrial encephalomyopathy widens the spectrum of AIFM1 disorders

To date, 3 AIFM1 (apoptosis inducing factor mitochondrial 1, located on Xq26.1) mutations have been reported: 2 missense changes (c.923G>A/p.Gly308Glu; c.1478A>T/p.Glu493Val) and a 3-basepair deletion (c.601delAGA/p.Arg201del). Two mutations have been described in early-onset severe mitochondrial encephalomyopathy related to impaired oxidative phosphorylation.1,2 A third mutation is associated with Cowchock syndrome, or Charcot-Marie-Tooth X4 (CMTX4), a slowly progressive disorder characterized by axonal neuropathy, hearing loss, and mental retardation.3,4

Mutations in Epigenetic Regulation Genes Are a Major Cause of Overgrowth with Intellectual Disability

To explore the genetic architecture of human overgrowth syndromes and human growth control, we performed experimental and bioinformatic analyses of 710 individuals with overgrowth (height and/or head circumference ≥+2 SD) and intellectual disability (OGID). We identified a causal mutation in 1 of 14 genes in 50% (353/710). This includes HIST1H1E, encoding histone H1.4, which has not been associated with a developmental disorder previously. The pathogenic HIST1H1E mutations are predicted to result in a product that is less effective in neutralizing negatively charged linker DNA because it has a reduced net charge, and in DNA binding and protein-protein interactions because key residues are truncated. Functional network analyses demonstrated that epigenetic regulation is a prominent biological process dysregulated in individuals with OGID. Mutations in six epigenetic regulation genes—NSD1, EZH2, DNMT3A, CHD8, HIST1H1E, and EED—accounted for 44% of individuals (311/710). There was significant overlap between the 14 genes involved in OGID and 611 genes in regions identified in GWASs to be associated with height (p = 6.84 × 10−8), suggesting that a common variation impacting function of genes involved in OGID influences height at a population level. Increased cellular growth is a hallmark of cancer and there was striking overlap between the genes involved in OGID and 260 somatically mutated cancer driver genes (p = 1.75 × 10−14). However, the mutation spectra of genes involved in OGID and cancer differ, suggesting complex genotype-phenotype relationships. These data reveal insights into the genetic control of human growth and demonstrate that exome sequencing in OGID has a high diagnostic yield.

Novel mutations in IBA57 are associated with leukodystrophy and variable clinical phenotypes

Defects of the Fe/S cluster biosynthesis represent a subgroup of diseases affecting the mitochondrial energy metabolism. In the last years, mutations in four genes (NFU1, BOLA3, ISCA2 and IBA57) have been related to a new group of multiple mitochondrial dysfunction syndromes characterized by lactic acidosis, hyperglycinemia, multiple defects of the respiratory chain complexes, and impairment of four lipoic acid-dependent enzymes: α-ketoglutarate dehydrogenase complex, pyruvic dehydrogenase, branched-chain α-keto acid dehydrogenase complex and the H protein of the glycine cleavage system. Few patients have been reported with mutations in IBA57 and with variable clinical phenotype. Herein, we describe four unrelated patients carrying novel mutations in IBA57. All patients presented with combined or isolated defect of complex I and II. Clinical features varied widely, ranging from fatal infantile onset of the disease to acute and severe psychomotor regression after the first year of life. Brain MRI was characterized by cavitating leukodystrophy. The identified mutations were never reported previously and all had a dramatic effect on IBA57 stability. Our study contributes to expand the array of the genotypic variation of IBA57 and delineates the leukodystrophic pattern of IBA57 deficient patients.

Biallelic Mutations in DNM1L are Associated with a Slowly Progressive Infantile Encephalopathy

Mitochondria are highly dynamic organelles, undergoing continuous fission and fusion, and mitochondrial dynamics is important for several cellular functions. DNM1L is the most important mediator of mitochondrial fission, with a role also in peroxisome division. Few reports of patients with genetic defects in DNM1L have been published, most of them describing de novo dominant mutations. We identified compound heterozygous DNM1L variants in two brothers presenting with an infantile slowly progressive neurological impairment. One variant was a frame‐shift mutation, the other was a missense change, the pathogenicity of which was validated in a yeast model. Fluorescence microscopy revealed abnormally elongated mitochondria and aberrant peroxisomes in mutant fibroblasts, indicating impaired fission of these organelles. In conclusion, we described a recessive disease caused by DNM1L mutations, with a clinical phenotype resembling mitochondrial disorders but without any biochemical features typical of these syndromes (lactic acidosis, respiratory chain complex deficiency) or indicating a peroxisomal disorder.

Fukutin gene mutations in an Italian patient with early onset muscular dystrophy but no central nervous system involvement

Hypoglycosylation of α‐dystroglycan characterizes a subgroup of muscular dystrophies of variable severity, including Fukuyama congenital muscular dystrophy. We found fukutin gene mutations in a 4.5‐year‐old Italian patient, with reduced α‐dystroglycan expression, dystrophic features on muscle biopsy, hypotonia since birth, mild myopathy, but no brain involvement. Mutations in the fukutin gene can be associated with much milder phenotypes than classical Fukuyama congenital muscular dystrophy, and, although rare, can occur in non‐Japanese. Muscle Nerve, 2009

Neurological Disorders Associated with Striatal Lesions: Classification and Diagnostic Approach

Neostriatal abnormalities can be observed in a very large number of neurological conditions clinically dominated by the presence of movement disorders. The neuroradiological picture in some cases has been described as “bilateral striatal necrosis” (BSN). BSN represents a condition histo-pathologically defined by the involvement of the neostriata and characterized by initial swelling of putamina and caudates followed by degeneration and cellular necrosis. After the first description in 1975, numerous acquired and hereditary conditions have been associated with the presence of BSN. At the same time, a large number of disorders involving neostriata have been described as BSN, in some cases irrespective of the presence of signs of cavitation on MRI. As a consequence, the etiological spectrum and the nosographic boundaries of the syndrome have progressively become less clear. In this study, we review the clinical and radiological features of the conditions associated with MRI evidence of bilateral striatal lesions. Based on MRI findings, we have distinguished two groups of disorders: BSN and other neostriatal lesions (SL). This distinction is extremely helpful in narrowing the differential diagnosis to a small group of known conditions. The clinical picture and complementary exams will finally lead to the diagnosis. We provide an update on the etiological spectrum of BSN and propose a diagnostic flowchart for clinicians.

Mitochondrial Complex III Deficiency Caused by TTC19 Defects: Report of a Novel Mutation and Review of Literature

We report about a patient with infantile-onset neurodegenerative disease associated with isolated mitochondrial respiratory chain complex III (cIII) deficiency. The boy, now 13 years old, presented with language regression and ataxia at 4 years of age and then showed a progressive course resulting in the loss of autonomous gait and speaking during the following 2 years. Brain MRI disclosed bilateral striatal necrosis. Sequencing of a panel containing nuclear genes associated with cIII deficiency revealed a previously undescribed homozygous rearrangement (c.782_786delinsGAAAAG) in TTC19 gene, which results in a frameshift with premature termination (p.Glu261Glyfs(*)8). TTC19 protein was absent in patients fibroblasts. TTC19 encodes tetratricopeptide 19, a putative assembly factor for cIII. To date TTC19 mutations have been reported only in few cases, invariably associated with cIII deficiency, but presenting heterogeneous clinical phenotypes. We reviewed the genetic, biochemical, clinical and neuroradiological features of TTC19 mutant patients described to date.