Genomic, Proteomic, and Phenotypic Spectrum of Novel O-Sialoglycoprotein Endopeptidase Variant in Four Affected Individuals With Galloway-Mowat Syndrome.

Galloway-Mowat syndrome is a rare autosomal recessive disease characterized by a unique combination of renal and neurological manifestations, including early-onset steroid-resistant nephrotic syndrome, microcephaly, psychomotor delay, and gyral abnormalities of the brain. Most patients die during early childhood. Here, we identified a novel homozygous O-sialoglycoprotein endopeptidase (OSGEP) variant, NM_017807.3:c.973C>G (p.Arg325Gly), in four affected individuals in an extended consanguineous family from Saudi Arabia. We have described the detailed clinical characterization, brain imaging results, and muscle biopsy findings. The described phenotype varied from embryonic lethality to early pregnancy loss or death at the age of 9. Renal disease is often the cause of death. Protein modeling of this OSGEP variant confirmed its pathogenicity. In addition, proteomic analysis of the affected patients proposed a link between the KEOPS complex function and human pathology and suggested potential pathogenic mechanisms.

Exome Sequencing Reveals Novel TTN Variants in Saudi Patients with Congenital Titinopathies.

Aim: Our goal was to determine the genetic basis of early-onset myopathy in patients from two unrelated families. Materials and Methods: Whole-exome sequencing, autozygosity mapping, and confirmatory targeted Sanger sequencing were performed using genomic DNA extracted from blood samples from three myopathic patients of two unrelated families. Variant filtering and pathogenicity analyses were evaluated according to standard protocols and up-to-date pipelines applied at the King Faisal Specialist Hospital and Research Center. Results: A novel homozygous variant was detected in TTN gene within the first three M-line-encoding exons in a 9-year-old female in the first family who had delayed motor development and proximal weakness. Her 4-year-old affected brother, with the same homozygous variant, could not yet walk without help. This pathogenic nonsense variant is predicted to cause a premature stop during translation. In the second family we identified two novel variants as compound heterozygosites (a deletion and a variant affecting a canonical splice site) in an affected 9-year-old female with weakness that developed at age 3, in the second family. SpliceAI predicted the variants being splice-altering with high probability. These variants were fully segregated in the family. The deletion was found to be on the paternal allele, whereas the splicing variant was on the maternal allele. The patient's echocardiography revealed mitral valve prolapse with mild mitral regurgitation. Muscle histology showed minicores that were also confirmed by electron microscopy. Conclusion: Our study identified novel pathogenic variants in the TTN gene that are likely responsible for the phenotype of early-onset myopathy; hence, expanding genotype-phenotype relationship of titinopathies.

Ancient founder mutation in RUBCN: a second unrelated family confirms Salih ataxia (SCAR15).

BACKGROUND: Homozygous frameshift mutation in RUBCN (KIAA0226), known to result in endolysosomal machinery defects, has previously been reported in a single Saudi family with autosomal recessive spinocerebellar ataxia (Salih ataxia, SCAR15, OMIM # 615705). The present report describes the clinical, neurophysiologic, neuroimaging, and genetic findings in a second unrelated Saudi family with two affected children harboring identical homozygous frameshift mutation in the gene. It also explores and documents an ancient founder cerebellar ataxia mutation in the Arabian Peninsula. CASE PRESENTATION: The present family has two affected males (aged 6.5 and 17 years) with unsteady gait apparent since learning to walk at 2.5 and 3 years, respectively. The younger patient showed gait ataxia and normal reflexes. The older patient had saccadic eye movement, dysarthria, mild upper and lower limb and gait ataxia (on tandem walking), and enhanced reflexes in the lower limbs. Cognitive abilities were mildly impaired in the younger sibling (IQ 67) and borderline in the older patient (IQ 72). Nerve conduction studies were normal in both patients. MRI was normal at 2.5 years in the younger sibling. Brain MRI showed normal cerebellar volume and folia in the older sibling at the age of 6 years, and revealed minimal superior vermian atrophy at the age of 16 years. Autozygome and exome analysis showed both affected have previously reported homoallelic mutation in RUBCN (NM_014687:exon18:c.2624delC:p.A875fs), whereas the parents are carriers. Autozygosity mapping focused on smallest haplotype on chromosome 3 and mutation age analysis revealed the mutation occurred approximately 1550 years ago spanning about 62 generations. CONCLUSIONS: Our findings validate the slowly progressive phenotype of Salih ataxia (SCAR15, OMIM # 615705) by an additional family. Haplotype sharing attests to a common founder, an ancient RUBCN mutation in the Arab population.

Progressive Multifocal Leukoencephalopathy in the Absence of Typical Radiological Changes: Can We Make a Diagnosis?

BACKGROUND Progressive multifocal leukoencephalopathy (PML) is a serious opportunistic infectious disease with high morbidity and mortality. Its incidence in multiple sclerosis (MS) patients has risen since the introduction of disease modifying drugs. In the absence of a specific treatment, the outcome depends heavily on early diagnosis, which illustrates the importance of the role of characteristic brain magnetic resonance imaging (MRI). However, when relying mainly on MRI, the diagnosis of cases with atypical radiological changes may be missed or delayed. CASE REPORT A 32-year-old female diagnosed with elapsing remitting MS in 2009 was started on interferon-beta-1b that was escalated to natalizumab due to progression of the disease. Later, she was shifted to fingolimod as testing for John Cunningham polyoma virus (JCV) antibodies was positive. Three years later, she presented with a 3-week history of progressive walking impairment associated with twitching of her facial muscles and abnormal sensation all over her body that was associated with left hemi-paresis and sensory changes, in addition to truncal ataxia, which was treated with steroids as a relapse of MS. However, the patient continued to deteriorate and developed significant cognitive and behavioral changes. In view of this clinical picture, the diagnosis of PML was raised in spite of her atypical brain MRI features. Treatment with fingolimod was stopped and a sample of her cerebrospinal fluid was sent for JCV DNA analysis, which came back positive at 11 copies/mL. Treatment with mirtazepine and mefloquine was started, but the patient deteriorated further, and MRI showed severe changes consistent with immune reconstitution inflammatory syndrome. Intravenous steroids and intravenous immunoglobulin were given, and within a few weeks, the patient was stabilized and started to gradually improve. CONCLUSIONS In patients at risk for developing PML who present with typical clinical features, testing for JCV DNA is recommended even in the absence of typical radiological findings in order to prevent any delay in the diagnosis.

Biallelic mutations in human DCC cause developmental split-brain syndrome.

Motor, sensory, and integrative activities of the brain are coordinated by a series of midline-bridging neuronal commissures whose development is tightly regulated. Here we report a new human syndrome in which these commissures are widely disrupted, thus causing clinical manifestations of horizontal gaze palsy, scoliosis, and intellectual disability. Affected individuals were found to possess biallelic loss-of-function mutations in the gene encoding the axon-guidance receptor 'deleted in colorectal carcinoma' (DCC), which has been implicated in congenital mirror movements when it is mutated in the heterozygous state but whose biallelic loss-of-function human phenotype has not been reported. Structural MRI and diffusion tractography demonstrated broad disorganization of white-matter tracts throughout the human central nervous system (CNS), including loss of all commissural tracts at multiple levels of the neuraxis. Combined with data from animal models, these findings show that DCC is a master regulator of midline crossing and development of white-matter projections throughout the human CNS.

Hyperekplexia, microcephaly and simplified gyral pattern caused by novel ASNS mutations, case report.

BACKGROUND: Asparagine synthetase deficiency (OMIM# 615574) is a very rare newly described neurometabolic disorder characterized by congenital microcephaly and severe global developmental delay, associated with intractable seizures or hyperekplexia. Brain MRI typically shows cerebral atrophy with simplified gyral pattern and delayed myelination. Only 12 cases have been described to date. The disease is caused by homozygous or compound heterozygous mutations in the ASNS gene on chromosome 7q21. CASE PRESENTATION: Family 1 is a multiplex consanguineous family with five affected members, while Family 2 is simplex. One affected from each family was available for detailed phenotyping. Both patients (Patients 1 and 2) presented at birth with microcephaly and severe hyperekplexia, and were found to have gross brain malformation characterized by simplified gyral pattern, and hypoplastic cerebellum and pons. EEG showed no epileptiform discharge in Patient 2 but multifocal discharges in patient 1. Patient 2 is currently four years old with severe neurodevelopmental delay, quadriplegia and cortical blindness. Whole exome sequencing (WES) revealed a novel homozygous mutation in ASNS (NM_001178076.1) in each patient (c.970C > T:p.(Arg324*) and c.944A > G:p.(Tyr315Cys)). CONCLUSION: Our results expand the mutational spectrum of the recently described asparagine synthetase deficiency and show a remarkable clinical homogeneity among affected individuals, which should facilitate its recognition and molecular confirmation for pertinent and timely genetic counseling.

The association between petrous apex cephalocele and empty sella.

PURPOSE: Petrous apex cephalocele (PAC) is a rare lesion that has been linked to empty sella in several case reports. The aim of this study is to document the incidence of empty sella and PAC in consecutive brain MRI studies and study the association between these two lesions to better understand the underlying etiology of PAC. METHODS: A total of 2410 brain MRI studies were performed in our institution in the period from January 2011 to December 2011. After eliminating duplicated studies, a total of 2093 studies met our inclusion criteria. Retrospective analysis of patients' head MRI was performed by two radiologists independently to identify the presence of empty sella and/or PAC. RESULTS: Empty sella was found in 322 (15.4 %) patients. PAC was found in 111 (5.3 %) patients (age range 6-81 years) of which 87 were females and 24 were males. Of all the patients with PAC, 77 (69.4 %) patients had associated empty sella. Bilateral PAC was more common and seen in 77 patients. CONCLUSION: PAC is associated with empty sella, and both lesions are probably related to the same cause.

Partial duplication of chromosome 19 associated with syndromic duane retraction syndrome.

BACKGROUND: To evaluate possible monogenic and chromosomal anomalies in a patient with unilateral Duane retraction syndrome, modest dysmorphism, cerebral white matter abnormalities, and normal cognitive function. MATERIALS AND METHODS: Performing high-resolution array comparative genomic hybridization (array CGH) and sequencing of HOXA1, KIF21A, SALL4, and CHN1 genes. RESULTS: The proband had unilateral Duane retraction syndrome (DRS) type III on the right with low-set ears, prominent forehead, clinodactyly, and a history of frequent infections during early childhood. Motor development and cognitive function were normal. Parents were not related, and no other family member was similarly affected. MRI revealed multiple small areas of high signal on T2 weighted images in cerebral white matter oriented along white matter tracts. Sequencing of HOXA1, KIF21A, SALL4, and CHN1 did not reveal any mutation(s). Array CGH showed a 95 Kb de novo duplication on chromosome 19q13.4 encompassing four killer cell immunoglobulin-like receptor (KIR) genes. Conclusions. KIR genes have not previously been linked to a developmental syndrome, although they are known to be expressed in the human brain and brainstem and to be associated with certain infections and autoimmune diseases, including some affecting the nervous system. DRS and brain neuroimaging abnormalities may imply a central and peripheral oligodendrocyte abnormality related in some fashion to an immunomodulatory disturbance.

Ocular motility abnormalities in orbitofacial neurofibromatosis type 1.

PURPOSE: To evaluate the causes of ocular motility disturbances in a group of patients with orbitofacial neurofibromatosis (OFNF) with neurofibromas on the lid, brow, face, or in the orbit from infancy or early childhood. METHODS: The medical records of patients with OFNF from one institution were retrospectively reviewed; selected patients were reexamined. RESULTS: A total of 45 patients with unilateral OFNF and 4 with bilateral OFNF were included. Of these, 14 had no strabismus and relatively good vision, with no ductional abnormalities on either side despite large globes, sphenoid dysplasia, and neurofibromas in the orbit and/or cavernous sinus in many. The 8 patients with comitant strabismus also had no ductional abnormalities with a similar constellation of anatomic abnormalities, but these patients all had poor vision in at least one eye. The 27 patients with incomitant strabismus all had downward displacement of the globe and limited ductions. CONCLUSIONS: The pathologic anatomic changes associated with OFNF do not always cause ocular motility abnormalities: strabismus generally was not present when ocular motility was full and visual acuity was good. Comitant strabismus occurred in the setting of full ocular motility with reduced vision in at least one eye. Incomitant strabismus was always accompanied by reduced vision and a ductional abnormality in one or both eyes due to anatomic abnormalities of the orbit and skull.

HOXA1 Mutations are Not Commonly Associated with Non-Syndromic Deafness.

OBJECTIVE: Homozygous homeobox A1 (HOXA1) mutations cause a spectrum of abnormalities in humans including bilateral profound deafness. This study evaluates the possible role of HOXA1 mutations in familial, non-syndromic sensorineural deafness. METHODS: Forty-eight unrelated Middle Eastern families with either consanguinity or familial deafness were identified in a large deafness clinic, and the proband from each family was evaluated by chart review, audiogram, neuroimaging, and HOXA1 sequencing. RESULTS: All 48 probands had normal neuro-ophthalmologic and general medical examinations except for refractive errors. All had congenital non-syndromic sensorineural hearing loss that was symmetric bilaterally and profound (>90 dBHL) in 33 individuals and varied from 40 to 90 dBHL in the remainder. Thirty-nine of these individuals had neuroimaging studies, all documenting normal internal carotid arteries and normal 6th, 7th, and 8th cranial nerves bilaterally. Of these, 27 had normal internal ear structures with the remaining 12 having mild to modest developmental abnormalities of the cochlea, semicircular canals, and/or vestibular aqueduct. No patient had homozygous HOXA1 mutations. CONCLUSIONS: None of these patients with non-syndromic deafness had HOXA1 mutations. None had major inner ear anomalies, obvious cerebrovascular defects, or recognized congenital heart disease. HOXA1 is likely not a common cause of non-syndromic deafness in this Middle Eastern population.

Neurologic injury in isolated sulfite oxidase deficiency.

BACKGROUND: We review clinical, neuroimaging, and genetic information on six individuals with isolated sulfite oxidase deficiency (ISOD). METHODS: All patients were examined, and clinical records, biochemistry, neuroimaging, and sulfite oxidase gene (SUOX) sequencing were reviewed. RESULTS: Data was available on six individuals from four nuclear families affected by ISOD. Each individual began to seize within the first week of life. neurologic development was arrested at brainstem reflexes, and severe microcephaly developed rapidly. neuroimaging within days of birth revealed hypoplasia of the cerebellum and corpus callosum and damage to the supratentorial brain looking like severe hypoxic-ischemic injury that evolved into cystic hemispheric white matter changes. Affected individuals all had elevated urinary S-sulfocysteine and normal urinary xanthine and hypoxanthine levels diagnostic of ISOD. Genetic studies confirmed SUOX mutations in four patients. CONCLUSIONS: ISOD impairs systemic sulfite metabolism, and yet this genetic disease affects only the brain with damage that is commonly confused with the clinical and radiologic features of severe hypoxic-ischemic encephalopathy.Lésions neurologiques dans le déficit isolé en sulfite oxydase.

Xq26.3 microdeletion in a male with Wildervanck Syndrome.

BACKGROUND: Wildervanck Syndrome (WS; cervico-oculo-acoustic syndrome) consists of Duane retraction syndrome (DRS), the Klippel-Feil anomaly, and congenital deafness. It is much more common in females than males and could be due to an X-linked mutation that is lethal to hemizygous males. We present the genetic evaluation of a male with WS and his family. MATERIALS AND METHODS: Clinical evaluation and neuroimaging, sequencing of candidate genes, and array comparative genomic hybridization. RESULTS: The patient had bilateral type 1 DRS, fusion of almost the entire cervical spine, and bilateral severe sensorineural hearing loss due to bilateral cochlear dysplasia; he also had congenital heart disease requiring surgery. His parents were unrelated, and he had eight unaffected siblings. The patient had no mutation found by Sanger sequencing of HOXA1, KIF21A, SALL4, and CHN1. He had a 3kB deletion in the X-chromosome at Xq26.3 that was not found in his mother, one unaffected sibling, or 56 healthy controls of matching ethnicity. This deletion encompassed only one gene, Fibroblast Growth Factor Homologous Factor 13 (FGF13), which encodes a 216-amino acid protein that acts intracellularly in neurons throughout brain development. CONCLUSIONS: Analysis of this patient's phenotype and genotype open the possibility that X-chromosome deletions may be a cause of WS with larger deletions being lethal to males and that FGF13 mutations may be a cause of WS.

Partial chromosome 7 duplication with a phenotype mimicking the HOXA1 spectrum disorder.

PURPOSE: To evaluate possible monogenic and chromosomal anomalies in a patient with bilateral Duane retraction syndrome and hearing impairment resulting in a phenotype resembling the HOXA1 spectrum disorder. METHODS: Sequencing HOXA1 and performing high resolution array comparative genomic hybridization (arrayCGH). RESULTS: The proband had bilateral Duane retraction syndrome (DRS) with severe hearing loss bilaterally and an absent right vertebral artery, mimicking the major features of the Bosley-Salih-Alorainy variant of the HOXA1 spectrum. However, he also had developmental delay, mild mental retardation, and seizures. His parents were not related, but his father had milder sensorineural hearing loss bilaterally, and two paternal uncles and a paternal cousin had seizures. Neuroimaging revealed moderate maldevelopment of inner ear bony anatomy bilaterally. HOXA1 sequencing was normal, but arrayCGH revealed a small partial duplication of chromosome 7 encompassing only the PTPRN2 gene (protein tyrosine phosphatase, receptor type, N polypeptide 2) that was not present in his parents, an unaffected brother, or 53 normal ethnically-matched individuals. CONCLUSIONS: PTPRN2 is not yet linked to a genetic syndrome, although its expression has been identified in the adult human brain, in certain tumors, and in association with type 1 diabetes mellitus. The phenotype of this patient is strikingly similar to, but not identical to, that of the HOXA1 spectrum disorder. The findings in this patient raise the possibility that PTPRN2 may be active during early development of the human brainstem and that its overexpression may cause bilateral DRS with hearing loss as occurs in patients with homozygous HOXA1 mutations.

A novel syndrome of lethal familial hyperekplexia associated with brain malformation.

BACKGROUND: Hyperekplexia (HPX) is a rare non-epileptic disorder manifesting immediately after birth with exaggerated persistent startle reaction to unexpected auditory, somatosensory and visual stimuli, and non-habituating generalized flexor spasm in response to tapping of the nasal bridge (glabellar tap) which forms its clinical hallmark. The course of the disease is usually benign with spontaneous amelioration with age. The disorder results from aberrant glycinergic neurotransmission, and several mutations were reported in the genes encoding glycine receptor (GlyR) α1 and ß subunits, glycine transporter GlyT2 as well as two other proteins involved in glycinergic neurotransmission gephyrin and collybistin. METHODS: The phenotype of six newborns, belonging to Saudi Arabian kindred with close consanguineous marriages, who presented with hyperekplexia associated with severe brain malformation, is described. DNA samples were available from two patients, and homozygosity scan to determine overlap with known hyperkplexia genes was performed. RESULTS: The kindred consisted of two brothers married to their cousin sisters, each with three affected children who presented antenatally with excessive fetal movements. Postnatally, they were found to have microcephaly, severe hyperekplexia and gross brain malformation characterized by severe simplified gyral pattern and cerebellar underdevelopment. The EEG was normal and they responded to clonazepam. All of the six patients died within six weeks. Laboratory investigations, including metabolic screen, were unremarkable. None of the known hyperkplexia genes were present within the overlapping regions of homozygosity between the two patients for whom DNA samples were available. CONCLUSIONS: We present these cases as a novel syndrome of lethal familial autosomal recessive hyperekplexia associated with microcephaly and severe brain malformation.

Visual loss in orbitofacial neurofibromatosis type 1.

PURPOSE: On occasion, neurofibromas in neurofibromatosis type 1 may be present on the lid, brow, or face of an infant or child, a circumstance commonly referred to as "orbitofacial neurofibromatosis" (OFNF). The present study evaluates the causes and extent of visual loss in a group of patients with OFNF. DESIGN: Case series. PARTICIPANTS: Fifty-five patients with OFNF. METHODS: Retrospective medical record review and reexamination of selected patients from one institution. MAIN OUTCOME MEASURES: Visual acuity and identification of underlying cause of reduced vision. RESULTS: Fifty patients with unilateral OFNF (23 male, 27 female, aged 4-48 years at last visit) and 5 patients with bilateral OFNF (2 male, 3 female, aged 15-43 years) had adequate information available to assess afferent visual functioning. Nine patients (4 male, 5 female, aged 4-28 years) had optic pathway glioma (OPG) in addition to OFNF. Patients were followed as long as 27 years (mean 8.4 years). Thirty-nine patients (71% of total) had visual acuity of ≤20/60 on the side of OFNF involvement (or the side of worse OFNF involvement in patients with bilateral disease). One or more causes of amblyopia were present in 29 of these patients, 19 patients had organic disease of the eye (e.g., glaucoma or retinal detachment) or the afferent system (e.g., OPG), and 12 patients had correctable refractive errors. CONCLUSIONS: Visual loss in this OFNF cohort was common, typically profound, and usually multifactorial. Some causes of visual loss (including congenital glaucoma with buphthalmos and retinal detachment, disconjugate gaze due in part to distorted skull development causing strabismic amblyopia, and OPG) were difficult to treat adequately and tended to cause progressive, profound visual loss. Therefore, careful observation should be made during the period of visual immaturity for possible causes of amblyopia that might be treatable, such as refractive changes, occlusion of the visual axis, or congenital glaucoma. As affected individuals get older, physicians must be vigilant for the progression of optic nerve disease due to glaucoma or OPG and to the possibility that vision might be improved by refraction.

The neurology of carbonic anhydrase type II deficiency syndrome.

Carbonic anhydrase type II deficiency syndrome is an uncommon autosomal recessive disease with cardinal features including osteopetrosis, renal tubular acidosis and brain calcifications. We describe the neurological, neuro-ophthalmological and neuroradiological features of 23 individuals (10 males, 13 females; ages at final examination 2-29 years) from 10 unrelated consanguineous families with carbonic anhydrase type II deficiency syndrome due to homozygous intron 2 splice site mutation (the 'Arabic mutation'). All patients had osteopetrosis, renal tubular acidosis, developmental delay, short stature and craniofacial disproportion with large cranial vault and broad forehead. Mental retardation was present in approximately two-thirds and varied from mild to severe. General neurological examinations were unremarkable except for one patient with brisk deep tendon reflexes and two with severe mental retardation and spastic quadriparesis. Globes and retinae were normal, but optic nerve involvement was present in 23/46 eyes and was variable in severity, random in occurrence and statistically correlated with degree of optic canal narrowing. Ocular motility was full except for partial ductional limitations in two individuals. Saccadic abnormalities were present in two, while half of these patients had sensory or accommodative strabismus, and seven had congenital nystagmus. These abnormalities were most commonly associated with afferent disturbances, but a minor brainstem component to this disorder remains possible. All internal auditory canals were normal in size, and no patient had clinically significant hearing loss. Neuroimaging was performed in 18 patients and repeated over as long as 10 years. Brain calcification was generally progressive and followed a distinct distribution, involving predominantly basal ganglia and thalami and grey-white matter junction in frontal regions more than posterior regions. At least one child had no brain calcification at age 9 years, indicating that brain calcification may not always be present in carbonic anhydrase type II deficiency syndrome during childhood. Variability of brain calcification, cognitive disturbance and optic nerve involvement may imply additional genetic or epigenetic influences affecting the course of the disease. However, the overall phenotype of the disorder in this group of patients was somewhat less severe than reported previously, raising the possibility that early treatment of systemic acidosis with bicarbonate may be crucial in the outcome of this uncommon autosomal recessive problem.

Horizontal gaze palsy and progressive scoliosis without ROBO3 mutations.

BACKGROUND: To describe clinical and genetic observations in a patient with horizontal gaze palsy and progressive scoliosis (HGPPS) without identified mutations in the ROBO3 gene. MATERIALS AND METHODS: Neurologic and orthopedic evaluation of the proband; sequencing all exons, exon-intron boundaries, and promoter region of ROBO3 in the proband and his mother. Array CGH was also carried out in the proband and his mother to evaluate possible chromosomal deletion(s) and/or duplication(s). RESULTS: The proband had complete horizontal gaze restriction with full vertical gaze and small amplitude horizontal pendular nystagmus. He also had severe scoliosis and brainstem hypoplasia pathognomonic of HGPPS. However, complete sequencing of ROBO3 twice in both forward and reverse directions did not reveal any mutations. Array CGH investigation revealed no chromosomal abnormalities. CONCLUSIONS: This patient had clinical and neuroimaging characteristics considered pathognomonic of HGPPS and yet did not have ROBO3 mutations. A clinical misdiagnosis is unlikely in the absence of facial weakness (typical of Moebius syndrome), deafness (typical of the HOXA1 spectrum), or mental retardation (typical of other central decussation abnormalities). It is perhaps more likely that a phenotype identical to HGPPS can be caused by abnormalities in ROBO3 splice variant expression, by mutations of a gene other than ROBO3, or by some environmental or epigenetic factor(s) inhibiting the action of ROBO3 or its protein product in the developing brainstem.

Molecular and neurological characterizations of three Saudi families with lipoid proteinosis.

BACKGROUND: Lipoid proteinosis is a rare autosomal recessive disease characterized by cutaneous and mucosal lesions and hoarseness appearing in early childhood. It is caused by homozygous or compound heterozygous mutations in the ECM1 gene. The disease is largely uncharacterized in Arab population and the mutation(s) spectrum in the Arab population is largely unknown. We report the neurologic and neuroradiologic characteristics and ECM1 gene mutations of seven individuals with lipoid proteinosis (LP) from three unrelated consanguineous families. METHODS: Clinical, neurologic, and neuro-ophthalmologic examinations; skin histopathology; brain CT and MRI; and sequencing of the fullECM1 gene. RESULTS: All seven affected individuals had skin scarring and hoarseness from early childhood. The two children in Family 1 had worse skin involvement and worse hoarseness than affected children of Families 2 and 3. Both children in Family 1 were modestly mentally retarded, and one had typical calcifications of the amygdalae on CT scan. Affected individuals in Families 2 and 3 had no grossneurologic, neurodevelopmental, or neuroimaging abnormalities. Skin histopathology was compatible with LP in all three families. Sequencing the full coding region of ECM1 gene revealed two novel mutationsin Family 1 (c.1300-1301delAA) and Family 2 (p.Cys269Tyr) and in Family 3 a previously described 1163 bp deletion starting 34 bp into intron 8. CONCLUSIONS: These individuals illustrate the neurologic spectrum of LP, including variable mental retardation, personality changes, and mesial temporal calcificationand imply that significant neurologic involvement may be somewhat less common than previously thought. The cause of neurologic abnormalities was not clear from either neuroimaging or from what is known about ECM1 function. The severity of dermatologic abnormalities and hoarseness generally correlated with neurologic abnormalities, with Family 1 being somewhat more affected in all spheres than the other two families. Nevertheless, phenotype-genotype correlation was not obvious, possibly because of difficulty quantifying the neurologic phenotype and because of genetic complexity.