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Neurodegeneration with brain iron accumulation (NBIA) defines a wide spectrum of clinical entities characterized by iron accumulation in specific regions of the brain, predominantly in the basal ganglia. We evaluated the presence of FA2H and C19orf12 mutations in a cohort of 46 Italian patients with early onset NBIA, which were negative for mutations in the PANK2 and PLA2G6 genes. Follow-up molecular genetic and in vitro analyses were then performed. We did not find any mutations in the FA2H gene, although we identified 3 patients carrying novel mutations in the C19orf12 gene. The recent discovery of new genes responsible for NBIA extends the spectrum of the genetic investigation now available for these disorders and makes it possible to delineate a clearer clinical-genetic classification of different forms of this syndrome. A large fraction of patients still remain without a molecular genetics diagnosis, suggesting that additional NBIA genes are still to be discovered. © 2012 Elsevier Inc.

Human ciliopathies are hereditary conditions caused by defects of proteins expressed at the primary cilium. Among ciliopathies, Joubert syndrome and related disorders (JSRD), Meckel syndrome (MKS) and nephronophthisis (NPH) present clinical and genetic overlap, being allelic at several loci. One of the most interesting gene is TMEM67, encoding the transmembrane protein meckelin. We performed mutation analysis of TMEM67 in 341 probands, including 265 JSRD representative of all clinical subgroups and 76 MKS fetuses. We identified 33 distinct mutations, of which 20 were novel, in 8/10 (80%) JS with liver involvement (COACH phenotype) and 12/76 (16%) MKS fetuses. No mutations were found in other JSRD subtypes, confirming the strong association between TMEM67 mutations and liver involvement. Literature review of all published TMEM67 mutated cases was performed to delineate genotype-phenotype correlates. In particular, comparison of the types of mutations and their distribution along the gene in lethal versus non lethal phenotypes showed in MKS patients a significant enrichment of missense mutations falling in TMEM67 exons 8 to 15, especially when in combination with a truncating mutation. These exons encode for a region of unknown function in the extracellular domain of meckelin.

CLN1 disease (OMIM # 256730) is an early childhood ceroid-lipofuscinosis associated with mutated CLN1, whose product Palmitoyl-Protein Thioesterase 1 (PPT1) is a lysosomal enzyme involved in the removal of palmitate residues from S-acylated proteins. In neurons, PPT1 expression is also linked to synaptic compartments. The aim of this study was to unravel molecular signatures connected to CLN1. We utilized SH-SY5Y neuroblastoma cells overexpressing wild type CLN1 (SH-p. wtCLN1) and five selected CLN1 patients' mutations. The cellular distribution of wtPPT1 was consistent with regular processing of endogenous protein, partially detected inside Lysosomal Associated Membrane Protein 2 (LAMP2) positive vesicles, while the mutants displayed more diffuse cytoplasmic pattern. Transcriptomic profiling revealed 802 differentially expressed genes (DEGs) in SH-p. wtCLN1 (as compared to empty-vector transfected cells), whereas the number of DEGs detected in the two mutants (p. L222P and p. M57Nfs * 45) was significantly lower. Bioinformatic scrutiny linked DEGs with neurite formation and neuronal transmission. Specifically, neuritogenesis and proliferation of neuronal processes were predicted to be hampered in the wtCLN1 overexpressing cell line, and these findings were corroborated by morphological investigations. Palmitoylation survey identified 113 palmitoylated protein-encoding genes in SH-p. wtCLN1, including 25 ones simultaneously assigned to axonal growth and synaptic compartments. A remarkable decrease in the expression of palmitoylated proteins, functionally related to axonal elongation (GAP43, CRMP1 and NEFM) and of the synaptic marker SNAP25, specifically in SH-p. wtCLN1 cells was confirmed by immunoblotting. Subsequent, bioinformatic network survey of DEGs assigned to the synaptic annotations linked 81 DEGs, including 23 ones encoding for palmitoylated proteins. Results obtained in this experimental setting outlined two affected functional modules (connected to the axonal and synaptic compartments), which can be associated with an altered gene dosage of wtCLN1. Moreover, these modules were interrelated with the pathological effects associated with loss of PPT1 function, similarly as observed in the Ppt1 knockout mice and patients with CLN1 disease.

Aim To characterize the phenotypic profile of a cohort of children affected with CLN5, a rare form of neuronal ceroid-lipofuscinosis (NCL), and to trace the features of the natural history of the disease. Method Records of 15 children (nine males, six females) were obtained from the data sets of the DEM-CHILD International NCL Registry. Disease progression was measured by rating six functional domains at different time points along the disease course. All patients underwent mutation analysis of the CLN5 gene and ultrastructural investigations of peripheral tissues. Expression of the gene product, pCLN5, was characterized in vitro in six patients. Results Disease onset was at 2 to 7 years 6 months of age: impaired learning and cognition were the most common early symptoms. Seizures occurred relatively late (median age 8y) and were the presenting symptoms in two children. Nine mutations were detected in 30 alleles, including six mutations predicting a truncated protein. Mixed cytosomes were observed by electron microscopy. Differences of disease progression were observed in two groups of patients and could be related to their genetic profile. Interpretation Clinical features in a multicentre cohort of patients with CLN5 confirm that cognitive difficulties are early clinical markers of this condition. Severe mutations were associated with a more rapid decline of neurological function.

Introduction: Adult-onset neuronal ceroid lipofuscinoses (ANCL) are a group of rare inherited neurodegenerative diseases of early adulthood, named after the presence of intralysosomal autofluorescent lipopigment with characteristic ultrastructural features in neurons and other cell types. Over the last decade, six ANCL genes have been identified, three of them being related to exclusively adult-onset phenotypes, the remaining three shared with childhood-onset NCL (CNCL).Areas covered: Even in the molecular era, the contribution of neuropathological assessment is essential since genetic heterogeneity foresees new genes to be detected and validated. No disease-modifying therapy (DMT) is available for neuronal ceroid lipofuscinoses (NCL), but patients may benefit from improved symptomatic and supportive treatments, and recent advances in cellular and molecular biology (utilizing both cellular and animal models of the disease) have provided important contributions to the knowledge of NCL pathophysiolo...

Human SH-SY5Y neuroblastoma cells are widely utilized in in vitro studies to dissect out pathogenetic mechanisms of neurodegenerative disorders. These cells are considered as neuronal precursors and differentiate into more mature neuronal phenotypes under selected growth conditions. In this study, in order to decipher the pathways and cellular processes underlying neuroblastoma cell differentiation in vitro, we performed systematic transcriptomic (RNA-seq) and bioinformatic analysis of SH-SY5Y cells differentiated according to a two-step paradigm: retinoic acid treatment followed by enriched neurobasal medium. Categorization of 1989 differentially expressed genes (DEGs) identified in differentiated cells functionally linked them to changes in cell morphology including remodelling of plasma membrane and cytoskeleton, and neuritogenesis. Seventy-three DEGs were assigned to axonal guidance signalling pathway, and the expression of selected gene products such as neurotrophin receptors, the functionally related SLITRK6, and semaphorins, was validated by immunoblotting. Along with these findings, the differentiated cells exhibited an ability to elongate longer axonal process as assessed by the neuronal cytoskeletal markers biochemical characterization and morphometric evaluation. Recognition of molecular events occurring in differentiated SH-SY5Y cells is critical to accurately interpret the cellular responses to specific stimuli in studies on disease pathogenesis.

Neuronal Ceroid Lipofuscinoses (NCL) are genetically heterogeneous heritable neurodegenerative disorders with worldwide distribution. They are considered as childhood diseases; however rare adult onset forms are known. NCL have a progressive course, affecting visual, motor and cognitive functions, and are associated with myoclonic epilepsy; behavioural problems can be observed at the onset. The outcome is invariably 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 with characteristic ultrastructural features. The NCL are autosomal recessive diseases (but a rare autosomal dominant form of adult onset). Thirteen NCL associated genes have been identified so far, which allow a definite diagnosis to be reached and provide genetic counselling to the families. Still unidentified NCL genes are foreseen. Allelic heterogeneity is observed in some mutated genes; likewise phenotypic heterogeneity is seen in several NCL. The gene products are either soluble proteins (such as lysosomal enzymes) or membrane proteins related to lysosomes, endoplasmic reticulum, synaptic vesicles. Little is known about pathogenetic mechanisms, leading to storage formation and cell death. Current research is focusing on intracellular trafficking, neurotransmission and storage removal. No cure is available for any form. Innovative treatments led to some results in mouse models related to lysosome hydrolase defects. Evidences that autophagy, oxidative stress, excitotoxicity play roles in NCL cell pathology raise the possibility that selected steps of these processes might become target of treatments, and therefore modify the disease course.

In childhood the neuronal ceroid lipofuscinoses (NCL) are the most frequent lysosomal diseases and the most frequent neurodegenerative diseases but, in adulthood, they represent a small fraction among the neurodegenerative diseases. Their morphology is marked by: (i) loss of neurons, foremost in the cerebral and cerebellar cortices resulting in cerebral and cerebellar atrophy; (ii) an almost ubiquitous accumulation of lipopigments in nerve cells, but also in extracerebral tissues. Loss of cortical neurons is selective, indiscriminate depletion in early childhood forms occurring only at an advanced stage, whereas loss of neurons in subcortical grey-matter regions has not been quantitatively documented. Among the fourteen different forms of NCL described to date, CLN1 and CLN10 are marked by granular lipopigments, CLN2 by curvilinear profiles (CVPs), CLN3 by fingerprint profiles (FPPs), and other forms by a combination of these features. Among extracerebral tissues, lymphocytes, skin, rectum, skeletal muscle and, occasionally, conjunctiva are possible guiding targets for diagnostic identification, the precise type of NCL then requiring molecular analysis within the clinical and morphological context. Autosomal-recessive adult NCL has been linked molecularly to different childhood forms, i.e. CLN1, CLN5, and CLN6, whilst autosomal-dominant adult NCL, now designated as CLN4, is caused by a newly identified separate gene, DNAJC5. This article is part of a Special Issue entitled: The Neuronal Ceroid Lipofuscinoses or Batten Disease.

The neuronal ceroid lipofuscinoses (NCLs) are lysosomal storage disorders and together are the most common degenerative brain diseases in childhood. They are a group of disorders linked by the characteristic accumulation of abnormal storage material in neurons and other cell types, and a degenerative disease course. All NCLs are characterized by a combination of dementia, epilepsy, and motor decline. For most childhood NCLs, a progressive visual failure is also a core feature. The characteristics of these symptoms can vary and the age at disease onset ranges from birth to young adulthood. Genetic heterogeneity, with fourteen identified NCL genes and wide phenotypic variability render diagnosis difficult. A new NCL classification system based on the affected gene and the age at disease onset allows a precise and practical delineation of an individual patient's NCL type. A diagnostic algorithm to identify each NCL form is presented here. Precise NCL diagnosis is essential not only for genetic counseling, but also for the optimal delivery of care and information sharing with the family and other caregivers. These aspects are challenging because there are also potential long term complications which are specific to NCL type. Therefore care supported by a specifically experienced team of clinicians is recommended. As the underlying pathophysiological mechanism is still unclear for all NCL forms, the development of curative therapies remains difficult. This article is part of a Special Issue entitled: The neuronal ceroid lipofuscinoses or Batten Disease.

Purpose A small case series with a neurodegenerative disorder involving central nervous system and related to Seipin mutations was recently reported. Herein we describe clinical and EEG features of three patients presenting with Progressive Myoclonus Epilepsy (PME) and Congenital Generalized Lipodystrophy type 2 (CGL2) related to novel Seipin mutations. Methods The EEG-clinical picture was evaluated at epilepsy onset and in the follow-up period. The molecular analysis of BSCL2 , Laforin and Malin genes was performed to patients and/or their parents by Denaturing High Performance Liquid Chromatography and automated nucleotide sequencing. Skin specimens collected from a patient were processed for histochemical and ultrastructural analysis. Results The CGL2-PME syndrome co-segregated with two different BSCL2 genotypes: the homozygosity for c.782_783dupG involving exon 8 (two cases), or the compound heterozygosity for c.782_783dupG/c.828_829delAA (one case). Periodic-Acid Schiff positive osmiophilic material in the cytoplasm of fibrocytes and eccrine-gland cells were found in skin specimens. The lack of Lafora's bodies in skin specimens and the molecular analysis excluding mutations in Laforin and Malin genes ruled out Lafora disease. Conclusion The spectrum of CGL2 associated to BSCL2 gene mutations may include PMEs. Selected mutations in BSCL2 gene seem to be related to PMEs in patients with CGL2 phenotype.

Neuronal ceroid lipofuscinosis (NCL) are a group of progressive neurodegenerative disorders of childhood, characterized by the endo-lysosomal storage of autofluorescent material. Impaired mitochondrial function is often associated with neurodegeneration, possibly related to the apoptotic cascade. In this study we investigated the possible effects of lysosomal accumulation on the mitochondrial compartment in the fibroblasts of two NCL forms, CLN1 and CLN6. Fragmented mitochondrial reticulum was observed in all cells by using the intravital fluorescent marker Mitotracker, mainly in the perinuclear region. This was also associated with intense signal from the lysosomal markers Lysotracker and LAMP2. Likewise, mitochondria appeared to be reduced in number and shifted to the cell periphery by electron microscopy; moreover the mitochondrial markers VDCA and COX IV were reduced following quantitative Western blot analysis. Whilst there was no evidence of increased cell death under basal condition, we observed a significant increase in apoptotic nuclei following Staurosporine treatment in CLN1 cells only. In conclusion, the mitochondrial compartment is affected in NCL fibroblasts invitro, and CLN1 cells seem to be more vulnerable to the negative effects of stressed mitochondrial membrane than CLN6 cells.

Neuronal ceroid lipofuscinoses (NCLs) are characterized by epilepsy, visual failure, psychomotor deterioration, and accumulation of autofluorescent lipopigment. CLN8 mutations result in Northern epilepsy and Turkish variant late infantile NCL. We describe the clinical and neurophysiological findings of three patients with CLN8 mutations from Italy. In these patients, the onset of epilepsy occurred between 3 and 6 years of age, with myoclonic, tonic-clonic, and atypical absence seizures. Electroencephalograms revealed focal and/or generalized abnormalities. In all cases, blindness and progressive attenuation of the electroretinogram were observed. Magnetic resonance imaging revealed cerebral and cerebellar atrophy, thinning of the corpus callosum, deep white matter hyperintensity, and hyperintensity of the posterior limb of internal capsules. Skin biopsy revealed lysosomal storage in the cytoplasm of fibroblasts. The clinical picture of our cases resembles that of the Turkish patients and clearly differs from that of Northern epilepsy, which is marked by a prolonged course without myoclonus and visual loss. Definition of the clinical spectrum of this condition will aid in its recognition and have implications for diagnosis and genetic counseling.

We describe a case of a young patient suffering from a rapidly progressive cognitive decline, associated with delusions, myoclonus and seizures and with no family history for dementia. Clinical features, along with skin biopsy findings were overlapping storage disease; the genetic analysis, however, demonstrated a de novo presenilin 1 mutation. The present report suggests the usefulness of genetic determinations in early-onset cases of dementia, even without an autosomal dominant trait of inheritance; for these cases and their relatives an extensive genetic counselling should be recommended.

Neuronal ceroid lipofuscinoses (NCL) are the most commonly inherited progressive encephalopathies of childhood. Pathologically, they are characterized by endolysosomal storage with different ultrastructural features and biochemical compositions. The molecular mechanisms causing progressive neurodegeneration and common molecular pathways linking expression of different NCL genes are largely unknown. We analyzed proteome alterations in the brains of a mouse model of human infantile CLN1 disease—palmitoyl-protein thioesterase 1 (Ppt1) gene knockout and its wild-type age-matched counterpart at different stages: pre-symptomatic, symptomatic and advanced. For this purpose, we utilized a combination of laser capture microdissection-based quantitative liquid chromatography tandem mass spectrometry (MS) and matrix-assisted laser desorption/ionization time-of-flight MS imaging to quantify/visualize the changes in protein expression in disease-affected brain thalamus and cerebral cortex tissue slices, respectively. Proteomic profiling of the pre-symptomatic stage thalamus revealed alterations mostly in metabolic processes and inhibition of various neuronal functions, i.e., neuritogenesis. Down-regulation in dynamics associated with growth of plasma projections and cellular protrusions was further corroborated by findings from RNA sequencing of CLN1 patients’ fibroblasts. Changes detected at the symptomatic stage included: mitochondrial functions, synaptic vesicle transport, myelin proteome and signaling cascades, such as RhoA signaling. Considerable dysregulation of processes related to mitochondrial cell death, RhoA/Huntington’s disease signaling and myelin sheath breakdown were observed at the advanced stage of the disease. The identified changes in protein levels were further substantiated by bioinformatics and network approaches, immunohistochemistry on brain tissues and literature knowledge, thus identifying various functional modules affected in the CLN1 childhood encephalopathy.

Introduction In the literature there are few data about the use of pharmacological treatments (acute and prophylaxis) of primary headaches [migraine (M), tension-type headache (TTH)] in children [1]. Materials and methods Retrospective multicentre study conducted in 13 Juvenile Headache Centres; inclusion criteria: 1) diagnosis of primary headache (ICHD-II 2004); 2) stable headache pattern (>6 months). Results Seven hundred and thirty-two cases (349 m, 383 f), mean age: 12 years. Headache types: M 68%, TTH 21%, M+TTH 5%, other 4%. The statistical analysis, conducted on patients with M or TTH (n=659), considered: efficacy and safety of several drugs, any differences based on age, diagnosis and geographical distribution. Symptomatic treatment: 93% of children (M 95%, TTH 88%); type of drug: paracetamol (M 75%, TTH 75%), NSAIDs (M 51%, TTH 27%), triptans (M 6%, TTH 0%); good-excellent efficacy 72%, good-excellent tolerability 92%. Prophylaxis therapy: 52% of cases (M 45%, TTH 44%); type of drug: flunarizine (M 18%, TTH 2%), pizotifen (M 6%, TTH 0%), amitriptyline (M 3%, TTH 5%), anticonvulsants (M 7%, TTH 1%), supplements (M 31%, TTH 34%), melatonin (M 10%, TTH 10%); good-excellent efficacy 76%, good-excellent tolerability 85%. Discussion and conclusions In our study population M prevails (76%). Symptomatic therapy is frequently used (93%), more often in M than TTH, with good efficacy and tolerability for all drugs; it is ineffective only in 10% of cases (range 7-23%). The use of NSAIDs prevail in M than TTH; few M (6%) use triptans. Prophylaxis therapy, prescribed in about half of cases (both in M and TTH), is ineffective in 12% of cases, but is usually well tolerated; supplements (32%) and flunarizine (14%) prevail.

Neuronal ceroid lipofuscinoses (NCLs) are autosomal recessive neurodegenerative disorders typically characterized by the accumulation of autofluorescent material in tissues. On the basis of clinical features, age at onset, and molecular genetic defects, it is possible to distinguish at least nine forms. The CLN8 form was first described in Finland, where all the patients are homozygous for a p.Arg24Gly mutation in CLN8. More recently, it has been found that a subset of a Turkish variant of late infantile NCL (v-LINCL) is also associated with CLN8 mutations. To identify the molecular defect in Italian patients with v-LINCL, the CLN8 gene was directly sequenced in 10 patients. Controls were screened by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis. Five fluorescent-labeled microsatellite markers covering 1 cM around the gene were used for haplotype analysis. In three Italian v-LINCL patients, identified in a small area in southern Italy, we detected four new mutations in CLN8: c.66delG (p.Gly22fs), c.88G>C (p.Ala30Pro), c.473A>G (p.Tyr158Cys), and c.581A>G (p.Gln194Arg). The single-base deletion was found in two unrelated patients. The novel missense mutations were not identified in ethnically matched control chromosomes. Our findings expand the number of CLN8 variants and corroborate the notion that CLN8 patients are not confined to the Finnish population.

Introduction The are few data in the literature about the use of pharmacological and non-pharmacological therapies for primary headaches (migraine: M; tension-type headache: TTH) in children [1]. Materials and methods A retrospective study was conducted by twelve Juvenile Headache Centres; inclusion criteria: (1) diagnosis of primary headache (ICHD-II, 2004); (2) stable headache pattern ([6 months). Results Three hundred and twenty cases (163 M, 157 F) with mean age at interview of 11.1 ± 3.2 years (1–19 years). Headache types: M 71% (MO 62%, MA 6%, chronic M 3%), TTH 20% (ETTH 17%, CTTH 3%), and M + TTH 7%, other 2%. A) Symptomatic treatment used in 92% of cases (1 drug 57%, 2 drugs 26%, 3 drugs 9%); M 95% versus TTH 82% (p\0.0002); type of drug: paracetamol (P) (M 84%, TTH 73%), NSAIDs (M 46%, TTH 24%), triptans (T) (M 5%, TTH 0%); good–excellent efficacy 53%, good–excellent tolerability 86%. Prescriber: paediatrician (47%), child neuropsychiatry (41%), self-prescription (10%). (B) Prophylaxis therapy used in 46% of cases (1 drug 31%, 2 drugs 11%, 3 drugs 4%); M 53% versus CT 29% (p\0.01); type of drug: flunarizine (M 22% vs. TTH 2%, p\0.0002), pizotifen (M 7%, TTH 0%), propranolol (M 3%, TTH 0%), amitriptyline (M 1%, TTH 2%), anticonvulsants (M 7%, TTH 0%), supplements (M 25%, TTH 19%), melatonin (M 4%, TTH 6%); good–excellent efficacy 65%, good– excellent tolerability 80%. Prescriber: paediatrician (14%), child neuropsychiatrist (84%), no self-prescription. (C) Non-pharmacological treatments (N = 27, 8%): relaxation/biofeedback (30%), cognitive-behavioural therapy (22%), homeopathy (15%), treatment of malocclusion (15%), acupuncture (7%), psychotherapy (7%) and biofeedback (4%). (D) Rating more effective therapy: pharmacological symptomatic (57%) than prophylaxis combined with symptomatic (25%) or alone (16%); better tolerated therapy: pharmacological symptomatic (57%), than prophylaxis combined with symptomatic (22%) or alone (18%). Main expectations of the patient: effect on pain (62%), speed of action (30%) and lack of side effects (21%). Discussion and conclusions The study population consists predominantly of migraineurs (71%). The therapy most widely used was symptomatic (92%), especially P or NSAIDs, with limited use of T (E 5%) with good efficacy and tolerability. The prophylactic drugs most used were supplements (25%) and flunarizine (22%), while AEDs were rarely used (7%). The prophylaxis was ineffective in a third of migraineurs (28–34%), although often well tolerated (43–60%). The non-pharmacological therapy was not widely used (7%) and rarely preferred by patients (2–3%).

The axonal form of Charcot-Marie-Tooth neuropathy (CMT type 2) has autosomal dominant inheritance and is genetically heterogeneous. Only 2 genes are known so far. Two unrelated Caucasian pedigrees (from Russia and Belgium) had 2 distinct mutations in the neurofilament-light gene (NF-L)(CMT2E, chromosome 8p21); a single Japanese pedigree had a mutation in the kinesin 1B gene (KIF1B)(CMT2A, chromosome 1p35-p36). We aimed at investigating the epidemiological relevance of NF-L in an Italian series with CMT2. The series included 30 index cases with CMT2 diagnosed according to clinical, electrophysiological and pathological criteria, in whom we have ruled out mutations of MPZ/P0 and CX32. In the selected series, the entire coding region of NF-L was investigated by automated direct nucleotide sequencing. Direct molecular test of the novel identified mutation was performed by analyzing a restriction fragment length polymorphism (RFLP) for AatII. In a single five-generation pedigree, with 3 affected member examined, we identified a novel heterozygous c.64C > T transition which substitutes a proline with a serine at amino acid residue 22 (Pro22Ser). The mutation appeared to be pathogenic because it co-segregated with the disease in the pedigree and it was absent in more than 100 healthy controls. The amino acid change occurs in the N-terminal head domain which regulates the assembly of neurofilaments. The report emphasizes the etiological role of NF-L in CMT2.

Hereditary sensory and autonomic neuropathy type IV (HSAN-IV) and type V (HSAN-V) are autosomal recessive genetic disorders, both characterized by a lack of pain sensation. We report a girl with clinical and neurophysiological findings consistent with a diagnosis of HSAN-V. We sequenced her TRKA gene, encoding a receptor tyrosine kinase for nerve growth factor and responsible for HSAN-IV, but we could not detect any mutation. These data indicate that a gene (or genes) other than TRKA is probably responsible for HSAN-V in some patients.

It has been suggested that a genetic factor(s) or a familial predisposition may contribute to the clinical manifestations of disc herniation; moreover, no genetic linkage between spinal disc herniation and spastic paraplegia has ever been described. A family with consanguineous parents and four of eight sibs affected by multiple disc herniations and spastic paraplegia was clinically and genetically analysed. Surgery caused partial improvement in all of them. After the exclusion of type II collagen and vitamin D receptor genes and the recessive loci for HSPs, a genome wide search was performed with about 500 fluorescent markers. Positive lod score values were obtained for chromosome 6q22.31-q24.1, with evidence of three homozygous intervals. The maximum multipoint lod score of 3.28 was obtained in only one interval, between markers D6S1699 and D6S314. On the whole, a susceptibility locus for disc herniation and autosomal recessive spastic paraplegia was found on chromosome 6q23.3-q24.1. This is the first time that disc herniation and the associated neurological syndrome has been linked to a human chromosomal region.