Current Molecular Medicine (v.14, #8)

Revised Genetic Classification of Limb Girdle Muscular Dystrophies by F. Magri, S. Brajkovic, A. Govoni, R. Brusa, G.P. Comi (934-943).
Limb girdle muscular dystrophies (LGMD) are a heterogeneous group of inherited progressivemuscle disorders affecting predominantly the shoulder and pelvic girdle muscles. They present both withautosomal dominant and autosomal recessive patterns of inheritance. Recent development, including resultsfrom Next Generation Sequencing technology, expanded the number of recognised forms. Therefore a revisedgenetic classification that takes into account the novel entities is needed, allowing clinicians and researchers torefer to a common nomenclature for diagnostic and research purposes.

Adult-Onset Genetic Leukoencephalopathies. Focus on the More Recently Defined Forms by I. Di Donato, S. Banchi, A. Federico, M.T. Dotti (944-958).
Inherited white matter (WM) disorders include a heterogenous group of disorders affecting brainwhite matter and associated with myelin, axonal and glial cells or vascular pathology. Often a wide range ofoverlapping neurological manifestations possibly associated with variable systemic involvement are found inthese disorders making clinical diagnosis challenging. Advances in molecular genetics enabled theidentification of the responsible genes of an increasing number of previously undefined forms.;This review focuses on genetic leukoencephalopathies with exclusive adulthood presentation, most of whichhave an autosomal dominant inheritance. The most common forms are related to vascular pathology, such ascerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL),cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL),COL4A1-related leukoencephalopathy, retinal vasculopathy with cerebral leukodystrophy (RVCL), andpolycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy (PLOSL). Also cerebroretinalmicroangiopathy with cysts and calcifications (CRMCC), which presents a prevalent infantile onset, will bedetailed because of the vascular based myelin damage and the recent genetic characterization. Other adultonset (AO) leukoencephalopathies, such as the recently genetically defined hereditary diffuseleukoencephalopathy with axonal spheroids (HDLS), adult-onset autosomal dominant leukodystrophy (ADLD)due to LMNB1 duplication, adult polyglucosan body disease (APBD), and fragile X-associated tremor/ataxiasyndrome (FXTAS) will be detailed shortly. Short notes on the clinical and MRI features of late onset variantsof the classical infantile-onset leukodystrophies mostly related to metabolic disorders will also be given. Finally,palliative, curative and experimental treatment options are here summarized.

Metabolic Ataxias in Adults by A. Antenora, A. Filla, F.M. Santorelli, S. Peluso, F. Sacca, G. De Michele (959-970).
Metabolic ataxias are rare. They usually start in the childhood and often have autosomal recessiveinheritance. They may also present in adulthood. The diagnosis is important since some patients may besuccessfully managed with diet and treatments.

Late-Onset Glycogen Storage Disease Type 2 by M. Filosto, M.S. Cotelli, V. Vielmi, A. Todeschini, F. Rinaldi, S. Rota, M. Scarpelli, A. Padovani (971-978).
Glycogenosis II (GSDII) is an autosomal recessive lysosomal storage disorder resulting from acidalpha-glucosidase (GAA) deficiency, subsequent lysosomal accumulation of glycogen in muscles, impairmentof autophagic processes and progressive cardiac, motor and respiratory failure. The infantile form usuallyappears in the first month of life, progresses rapidly and presents with severe cardiac involvement andcomplete deficiency of alpha-glucosidase activity (< 1% of normal controls). The late-onset form ischaracterized by great variability of the phenotypical spectrum. Main findings are muscle weakness and severerespiratory insufficiency while cardiac involvement may be completely absent. Residual GAA enzyme activitymay correlate with severity of phenotype but many adult patients sharing the same mutations present with awide variability in residual enzyme activity, age of onset and rate of disease progression, thus supporting a rolefor other factors, i.e., post-translational modifications and modifier genes, in modulating disease presentation.;Enzyme replacement therapy (ERT) with alglucosidase alfa stabilizes the disease or improves muscle and/orrespiratory function. However, efficacy of ERT may be influenced by several factors including age when ERTbegins, extent of muscle damage, degree of defective autophagy, diversity in muscle fiber composition,difficulties in delivery of the therapeutic agent and antibody production. Further studies should be warranted toinvestigate factors determining the differences in clinical expression and therapeutic response in order toachieve better clinical and therapeutic management of these patients.

Common Genetic Conditions of Ischemic Stroke to Keep in Mind by M. Mancuso, D. Orsucci, E. Caldarazzo Ienco, M. Brondi, C. Simoncini, A. Chiti, V. Montano, E. Terni, N. Giannini, G. Siciliano, U. Bonuccelli (979-984).
Stroke is a complex disease resulting from the interplay of genetics and environment. In someinstances (mainly in young adults) stroke is the direct result of a monogenic disease. Among the monogeniccauses of stroke, the diseases which are most frequently encountered in the adult general neurologicalpractice are CADASIL, Fabry and mitochondrial diseases. Brain MRI and clinical features may frequently leadto a correct molecular diagnosis. Here we review the single-gene causes of ischemic stroke, with specialregard to the associated features which may help in the diagnostic approach.

Genetic Basis of Mitochondrial Optic Neuropathies by A. Maresca, L. Caporali, D. Strobbe, C. Zanna, D. Malavolta, C. La Morgia, M.L. Valentino, V. Carelli (985-992).
Over two decades have elapsed since the first mtDNA point mutation was associated with Leber'shereditary optic neuropathy (LHON) in 1988. We have subsequently witnessed a substantial understanding ofthe molecular basis of hereditary optic neuropathies, as well as of their clinical features and pathogenicmechanisms. It became clear that the large majority of genetic optic neuropathies have a primary or an indirectinvolvement of mitochondrial functions, justifying the definition of “mitochondrial optic neuropathies”. Despitethis progress many unsolved features remain to be understood, such as incomplete penetrance and variableclinical expressivity in LHON and dominant optic atrophy (DOA), gender prevalence in LHON, and complexgene/environment interactions in both LHON and DOA. The most recent advancement in our understanding ofthe molecular basis of mitochondrial optic neuropathies is the topic of this review. In particular, we analyze therole that mitochondrial biogenesis may play in the compensatory mechanisms that underlie incompletepenetrance and clinical expressivity, a scenario relevant for the possible design of future therapeuticapproaches.

Genetics of Alzheimer's Disease and Frontotemporal Dementia by B. Nacmias, I. Piaceri, S. Bagnoli, A. Tedde, S. Piacentini, S. Sorbi (993-1000).
The genetics of neurodegenerative diseases has an important role to clarify the pathogeneticmechanism, the diagnosis and finally the therapeutic and ethical implications.;Moreover, the genetic approach to the study of the main clinical forms of dementia (Alzheimer's disease-ADand Frontotemporal Dementia-FTD) suggests clinical guidelines for helping families to navigate through thesecomplexities. AD and FTD are multifactorial, genetically complex diseases involving many candidate genes.;Mutations in three genes (i.e. Amyloid Precursor Protein, APP; presenilin 1, PSEN1; presenilin 2, PSEN2)have been linked to 50% of all familial forms of AD (FAD).;Genome wide association studies (GWAS) have involved an increasing number of genes with a possible rolein the disease pathogenesis. Up to now, the genetics of familial forms of FTD is related to 7 genes: themicrotubule-associated protein tau (MAPT) progranulin (GRN), the valosin-containing protein (VCP),chromatin-modifying 2B (CHMP2B), the TARDNA binding protein 43 encoding gene (TARBDP), fused insarcoma (FUS) and the last hexanucleotide expansion repeats in the open reading frame of chromosome 9(C9orf72).;Pre-test counseling and the identification of genetic defects are important in both patients and asymptomatic atrisk family members.

Mitochondrial Disorders in Adults by A. Toscano, O. Musumeci (1001-1008).
Mitochondrial Disorders (MD) include a heterogeneous group of inherited disorders due to moleculardefects mainly affecting the mitochondrial oxidative phosphorylation system. Because the respiratory chain isunder control of two different genomes (nuclear DNA-nDNA and mitochondrial DNA-mtDNA), mitochondrialgenetics is quite complex and may justify the extreme clinical heterogeneity of these diseases. Clinically, MDusually involve multiple tissues, mainly affecting organs with high energy request as central nervous systemand skeletal muscle. They may present at any age, with different onsets, clinical presentation and progressionfrom an isolated involvement of vision or hearing to a multisystemic degenerative disorders with stroke-likeepisodes, peripheral neuropathy, ophthalmoparesis, seizures, cardiopathy, hepatopathy, endocrinopathies,etc. Over the last 50 years, it became evident that MD represent an important part of the general medicine.The complexity of clinical and genetic spectrum of those disorders is still increasing. The aim of this review isto walk through mitochondrial genetics, highlighting novel clinical entities.

Charcot-Marie-Tooth disease (CMT) and related neuropathies are a genetically highlyheterogeneous group of neurodegenerative disorders. CMT affects both the sensory and motor nerves, distalHereditary Motor Neuropathies (dHMN) are phenotypically similar disorders involving only motor nerves, whileHereditary Sensory and Autonomic Neuropathies (HSAN) are rare distinct disorders affecting sensory andsometimes autonomic nerves. Almost 70 genes have been identified as responsible for these disorders. It isastonishing to learn how diverse are the cellular sublocalisation and the functional roles of the encodedproteins of CMT-associated genes which all lead to similar disorders of the peripheral nervous system. Myelinformation and maintenance, mitochondrial dynamics, cytoskeleton organization, axonal transport, andvesicular trafficking are the most frequently involved pathways. However, dysfunction of several activities fromthe nucleus to the neuromuscular junction forms the basis for these hereditary neuropathies, making itchallenging predicting the functions of newly identified mutated genes. In this review we will discuss thefunction and related phenotypes of all the genes thus far associated with CMT, dHMN, and HSAN.

Bridging Over the Troubled Heterogeneity of SPG-Related Pathologies: Mechanisms Unite What Genetics Divide by A. Tessa, P.S. Denora, L. Racis, E. Storti, A. Orlacchio, F.M. Santorelli (1034-1042).
The hereditary spastic paraplegias (HSP) are characterized by spastic gait with weakness in thelegs and additional neurological or extra-neurological signs in &quot;complicated&quot; forms.;The past two decades have witnessed major advances in our understanding of their molecular bases with theidentification of a plethora of loci and the cloning of several SPG genes. Combined genetic and clinicalinformation has permitted a modern, molecularly-driven classification and an improved diagnosis, with severalnew data on the possible disease mechanisms. Further heterogeneity will rapidly emerge with the diffusion ofnext-generation sequencing platforms and, under the shadow of common themes in the pathogenesis, newtherapeutic options will likely emerge for a great number of patients.

Neuronal Ceroid Lipofuscinosis: The Increasing Spectrum of an Old Disease by A. Simonati, F. Pezzini, F. Moro, F.M. Santorelli (1043-1051).
Neuronal Ceroid Lipofuscinoses (NCL) are genetically heterogeneous heritable neurodegenerativedisorders with worldwide distribution. They are considered as childhood diseases; however rare adult onsetforms are known. NCL have a progressive course, affecting visual, motor and cognitive functions, and areassociated with myoclonic epilepsy; behavioural problems can be observed at the onset. The outcome isinvariably fatal, mostly during the second or third decade. The denomination is based on pathological criteria,i.e. the presence of intralysosomal storage of autofluorescent lipopigment of glycoprotein origin withcharacteristic ultrastructural features. The NCL are autosomal recessive diseases (but a rare autosomaldominant form of adult onset). Thirteen NCL associated genes have been identified so far, which allow adefinite diagnosis to be reached and provide genetic counselling to the families. Still unidentified NCL genesare foreseen. Allelic heterogeneity is observed in some mutated genes; likewise phenotypic heterogeneity isseen in several NCL. The gene products are either soluble proteins (such as lysosomal enzymes) ormembrane proteins related to lysosomes, endoplasmic reticulum, synaptic vesicles. Little is known aboutpathogenetic mechanisms, leading to storage formation and cell death. Current research is focusing onintracellular trafficking, neurotransmission and storage removal. No cure is available for any form. Innovativetreatments led to some results in mouse models related to lysosome hydrolase defects. Evidences thatautophagy, oxidative stress, excitotoxicity play roles in NCL cell pathology raise the possibility that selectedsteps of these processes might become target of treatments, and therefore modify the disease course.

Facioscapulohumeral Muscular Dystrophy: More Complex than it Appears by G. Ricci, M. Zatz, R. Tupler (1052-1068).
Facioscapulohumeral muscular dystrophy (FSHD) has been classified as an autosomal dominantmyopathy, linked to rearrangements in an array of 3.3 kb tandemly repeated DNA elements (D4Z4) located atthe 4q subtelomere (4q35). For the last 20 years, the diagnosis of FSHD has been confirmed in clinicalpractice by the detection of one D4Z4 allele with a reduced number (≤8) of repeats at 4q35. Although wideinter- and intra-familial clinical variability was found in subjects carrying D4Z4 alleles of reduced size, this DNAtesting has been considered highly sensitive and specific. However, several exceptions to this general rulehave been reported. Specifically, FSHD families with asymptomatic relatives carrying D4Z4 reduced alleles,FSHD genealogies with subjects affected with other neuromuscular disorders and FSHD affected patientscarrying D4Z4 alleles of normal size have been described. In order to explain these findings, it has beenproposed that the reduction of D4Z4 repeats at 4q35 could be pathogenic only in certain chromosomalbackgrounds, defined as “permissive” specific haplotypes. However, our most recent studies show that thecurrent DNA signature of FSHD is a common polymorphism and that in FSHD families the risk of developingFSHD for carriers of D4Z4 reduced alleles (DRA) depends on additional factors besides the 4q35 locus. Thesefindings highlight the necessity to re-evaluate the significance and the predictive value of DRA, not only forresearch but also in clinical practice. Further clinical and genetic analysis of FSHD families will be extremelyimportant for studies aiming at dissecting the complexity of FSHD.

Mitochondrial Diseases in Childhood by A. Ardissone, E. Lamantea, F. Invernizzi, M. Zeviani, S. Genitrini, I. Moroni, G. Uziel (1069-1078).
Mitochondrial disorders are a group of heterogeneous diseases associated with abnormalities of theoxidative phosphorylation (OXPHOS), the most important source of energy for the cell. The number ofmitochondrial syndromes and of identified causative genes is constantly increasing. Taken as a whole they areamong the most frequent genetic diseases in humans at any age. The respiratory chain is the only metabolicpathway under double genome control and molecular genetics of these disorders is complicated by theexistence of strict interactions between mitochondrial DNA and nuclear DNA. In childhood and infancy, clinicalpresentation differs from mitochondrial disorders with adult onset. The phenotypes are much more severe,often involving brain, frequently presenting as multisystemic disorders and seldom as isolated myopathy.Mutations in nDNA are more frequent than in adulthood.;The major phenotypes presenting in infancy are here correlated with genetic defects and biochemical data withthe aim to facilitate diagnosis work-up.

Parkinson Disease (PD) is a common neurodegenerative disorder of intricate etiology, caused byprogressive loss of aminergic neurons and accumulation of Lewy bodies. The predominant role of genetics inthe etiology of the disease has emerged since the identification of the first pathogenetic mutation in SNCA(alpha-synuclein) gene, back in 1997. Mendelian parkinsonisms, a minority among all PD forms, have beendeeply investigated, with 19 loci identified. More recently, genome wide association studies have providedconvincing evidence that variants in some of these genes, as well as in other genes, may confer an increasedrisk for late onset, sporadic PD. Moreover, the finding that heterozygous mutations in the GBA gene (mutatedin Gaucher disease) are among the strongest genetic susceptibility factors for PD, has widened the scenario ofPD genetic background to enclose a number of genes previously associated to distinct disorders, such asgenes causative of spinocerebellar ataxias, mitochondrial disorders and fragile X syndrome. At present, thegenetic basis of PD defines a continuum from purely mendelian forms (such as those caused by autosomalrecessive genes) to multifactorial inheritance, resulting from the variable interplay of many distinct geneticvariants and environmental factors.

Amyotrophic Lateral Sclerosis: A Genetic Point of View by C. Carlesi, E. Caldarazzo Ienco, M. Mancuso, G. Siciliano (1089-1101).
In the last twenty years the rapid advances in neurogenetic have revolutionized not only themolecular, pathological, inheritance but also the clinical concept of ALS.;Here we review the current genetic breakthrough in familial and sporadic ALS, considering how this knowledgehas allowed widening of the scenario on the possible pathogenic disease mechanisms and betterunderstanding of the relationship between the genetic, pathological and clinical subtypes.