A new missense variant in RAB3GAP2 in a family with muscular dystrophy-short stature and defective autophagy: An expansion of the micro/Martsolf spectrum or a new phenotype?

We describe a sibling pair of Mennonite origin born from consanguineous parentage with a likely new phenotype of limb-girdle muscular dystrophy, short stature, ptosis, and tracheomalacia. Exome sequencing in the affected subjects identified a novel homozygous RAB3GAP2 missense variant as the potential causal variant. As RAB3GAP2 has been recently shown to be involved in the autophagy process, we analyzed patient-derived fibroblasts by fluorescence microscopy and demonstrated defective autophagic flux under rapamycin and serum starvation conditions when compared with wild-type cells. The phenotype in the siblings described here is distinct from Martsolf and Warburg's micro syndromes, the currently known diseases arising from RAB3GAP2 pathogenic variants. Thus, this work describes a potentially novel recessive phenotype associated with a RAB3GAP2 defect and manifesting as a muscular dystrophy-short stature disorder with no ocular anomalies. Functional analyses indicated defective autophagy in patient-derived fibroblasts, supporting the involvement of RAB3GAP2 in the etiology of this disorder. Our results contribute to a better characterization of the Martsolf/micro spectrum phenotype.

A Diagnostic Approach to Spastic ataxia Syndromes.

Spastic ataxia is characterized by the combination of cerebellar ataxia with spasticity and other pyramidal features. It is the hallmark of some hereditary ataxias, but it can also occur in some spastic paraplegias and acquired conditions. It often presents with heterogenous clinical features with other neurologic and non-neurological symptoms, resulting in complex phenotypes. In this review, the differential diagnosis of spastic ataxias are discussed and classified in accordance with inheritance. Establishing an organized classification method based on mode inheritance is fundamental for the approach to patients with these syndromes. For each differential, the clinical features, neuroimaging and genetic aspects are reviewed. A diagnostic approach for spastic ataxias is then proposed.

Ophthalmological changes in hereditary spastic paraplegia and other genetic diseases with spastic paraplegia.

Ophthalmological abnormalities may occur in specific subtypes of hereditary spastic paraplegia (HSP) and in genetic diseases that present with spastic paraplegia mimicking HSP. These ophthalmological changes may precede the motor symptoms and include pigmentary retinal degeneration, ophthalmoplegia, optic atrophy, cataracts and nystagmus. Some ophthalmological abnormalities are more prevalent in specific forms of HSP. Considering that the diagnosis of HSP is usually difficult and complex, specific ophthalmological changes may guide the genetic testing. There are other genetic diseases such as autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS), X-linked adrenoleukodystrophy and spastic paraplegia, optic atrophy and neuropathy (SPOAN) that may mimic HSP and also may present with specific ophthalmological changes. In this article, we review the main ophthalmological changes observed in patients with HSP and HSP-like disorders.

A novel complex neurological phenotype due to a homozygous mutation in FDX2.

Defects in iron-sulphur [Fe-S] cluster biogenesis are increasingly recognized as causing neurological disease. Mutations in a number of genes that encode proteins involved in mitochondrial [Fe-S] protein assembly lead to complex neurological phenotypes. One class of proteins essential in the early cluster assembly are ferredoxins. FDX2 is ubiquitously expressed and is essential in the de novo formation of [2Fe-2S] clusters in humans. We describe and genetically define a novel complex neurological syndrome identified in two Brazilian families, with a novel homozygous mutation in FDX2. Patients were clinically evaluated, underwent MRI, nerve conduction studies, EMG and muscle biopsy. To define the genetic aetiology, a combination of homozygosity mapping and whole exome sequencing was performed. We identified six patients from two apparently unrelated families with autosomal recessive inheritance of a complex neurological phenotype involving optic atrophy and nystagmus developing by age 3, followed by myopathy and recurrent episodes of cramps, myalgia and muscle weakness in the first or second decade of life. Sensory-motor axonal neuropathy led to progressive distal weakness. MRI disclosed a reversible or partially reversible leukoencephalopathy. Muscle biopsy demonstrated an unusual pattern of regional succinate dehydrogenase and cytochrome c oxidase deficiency with iron accumulation. The phenotype was mapped in both families to the same homozygous missense mutation in FDX2 (c.431C > T, p.P144L). The deleterious effect of the mutation was validated by real-time reverse transcription polymerase chain reaction and western blot analysis, which demonstrated normal expression of FDX2 mRNA but severely reduced expression of FDX2 protein in muscle tissue. This study describes a novel complex neurological phenotype with unusual MRI and muscle biopsy features, conclusively mapped to a mutation in FDX2, which encodes a ubiquitously expressed mitochondrial ferredoxin essential for early [Fe-S] cluster biogenesis.

Nerve conduction studies in spastic paraplegia, optic atrophy, and neuropathy (SPOAN) syndrome.

INTRODUCTION: SPOAN (spastic paraplegia, optic atrophy, and neuropathy) syndrome is an autosomal recessive neurodegenerative disorder identified in a large consanguineous Brazilian family. METHODS: Twenty-seven patients with SPOAN syndrome (20 women), aged 4-58 years, underwent nerve conduction studies (NCS) of the median, ulnar, tibial, and fibular nerves, and sensory NCS of the median, ulnar, radial, sural, and superficial fibular nerves. RESULTS: Sensory nerve action potentials were absent in the lower limbs and absent in >80% of upper limbs. Motor NCS had reduced amplitudes and borderline velocities in the upper limbs and absent compound muscle action potentials (CMAPs) in the lower limbs. CONCLUSIONS: The neuropathy in SPOAN syndrome is a severe, early-onset sensory-motor axonal polyneuropathy. Normal NCS seem to rule-out this condition.

New RAB3GAP1 mutations in patients with Warburg Micro Syndrome from different ethnic backgrounds and a possible founder effect in the Danish.

Warburg Micro Syndrome is a rare, autosomal recessive syndrome characterized by microcephaly, microphthalmia, microcornia, congenital cataracts, optic atrophy, cortical dysplasia, in particular corpus callosum hypoplasia, severe mental retardation, spastic diplegia, and hypogonadism. We have found five new mutations in the RAB3GAP1 gene in seven patients with suspected Micro Syndrome from families with Turkish, Palestinian, Danish, and Guatemalan backgrounds. A thorough clinical investigation of the patients has allowed the delineation of symptoms that are consistently present in the patients and may aid the differential diagnosis of Micro Syndrome for patients in the future. All patients had postnatal microcephaly, micropthalmia, microcornia, bilateral congenital cataracts, short palpebral fissures, optic atrophy, severe mental retardation, and congenital hypotonia with subsequent spasticity. Only one patient had microcephaly at birth, highlighting the fact that congenital microcephaly is not a consistent feature of Micro syndrome. Analysis of the brain magnetic resonance imagings (MRIs) revealed a consistent pattern of polymicrogyria in the frontal and parietal lobes, wide sylvian fissures, a thin hypoplastic corpus callosum, and increased subdural spaces. All patients were homozygous for the mutations detected and all mutations were predicted to result in a truncated RAB3GAP1 protein. The analysis of nine polymorphic markers flanking the RAB3GAP1 gene showed that the mutation c.1410C>A (p.Tyr470X), for which a Danish patient was homozygous, occurred on a haplotype that is shared by the unrelated heterozygous parents of the patient. This suggests a possible founder effect for this mutation in the Danish population.

Spastic paraplegia, optic atrophy, and neuropathy: new observations, locus refinement, and exclusion of candidate genes.

SPOAN is an autosomal recessive neurodegenerative disorder which was recently characterized by our group in a large inbred Brazilian family with 25 affected individuals. This condition is clinically defined by: 1. congenital optic atrophy; 2. progressive spastic paraplegia with onset in infancy; and 3. progressive motor and sensory axonal neuropathy. Overall, we are now aware of 68 SPOAN patients (45 females and 23 males, with age ranging from 5 to 72 years), 44 of which are presented here for the first time. They were all born in the same geographic micro region. Those 68 patients belong to 43 sibships, 40 of which exhibit parental consanguinity. Sixty-one patients were fully clinically evaluated and 64 were included in the genetic investigation. All molecularly studied patients are homozygotes for D11S1889 at 11q13. This enabled us to reduce the critical region for the SPOAN gene from 4.8 to 2.3 Mb, with a maximum two point lod score of 33.2 (with marker D11S987) and of 27.0 (with marker D11S1889). Three genes located in this newly defined critical region were sequenced, but no pathogenic mutation was detected. The gene responsible for SPOAN remains elusive.

Triple A or Allgrove syndrome. A case report with ophthalmic abnormalities and a novel mutation in the AAAS gene.

PURPOSE: Triple A syndrome is a rare autosomal recessive disease characterized by achalasia, alacrima, adrenocorticotrophic hormone resistant adrenal failure and some neurologic abnormalities. We report a nine year old patient with alacrima, optic atrophy and achalasia with mutation in the AAAS gene. METHODS: PCR amplification of the complete coding sequence as well as the exon-intron junctions of AAAS gene was performed in DNA from the patient and his parents. RESULTS: AAAS gene analysis demonstrated a homozygous A to G mutation at nucleotide position 122 in exon 1 in DNA from the patient. CONCLUSIONS: The novel mutation described confirms the diagnosis.

GAPO syndrome: three new Brazilian cases, additional osseous manifestations, and review of the literature.

The GAPO syndrome is an extremely rare autosomal recessive disease that presents as main characteristics evident growth retardation, alopecia, pseudoanodontia, progressive optic atrophy and a typical face. Until now, only 30 patients have been reported in the medical literature (nine of them from Brazil, including the three cases described in the present article). This study describes three siblings with GAPO syndrome, two female and one male, the children of consanguineous parents (first-degree cousins, inbreeding F = 1/16), who are older than the previously described patients, presenting the characteristic phenotype besides serious bone alterations in the lower limbs, which had not yet been observed.

Dental findings in GAPO syndrome: case report.

This article reports the case of a young female adult with GAPO syndrome who presented as a peculiar dental finding unerupted primary and permanent dentitions, which resembled total anodontia on clinical examination. A cephalometric analysis was performed to investigate the alterations in facial bone development. This is the 9th GAPO syndrome case reported in a Brazilian patient.

Dental findings in GAPO syndrome: case report

This article reports the case of a young female adult with GAPO syndrome who presented as a peculiar dental finding unerupted primary and permanent dentitions, which resembled total anodontia on clinical examination. A cephalometric analysis was performed to investigate the alterations in facial bone development. This is the 9th GAPO syndrome case reported in a Brazilian patient.

Este artigo relata o caso de um jovem paciente, gênero feminino, portadora da síndrome de GAPO, apresentando impacções dos dentes decíduos e permanentes, sugerindo anodontia total no exame clínico. Foi realizada uma análise cefalométrica para investigar as alterações no desenvolvimento ósseo facial. Este é o nono caso descrito no Brasil

Ophthalmic aspects of GAPO syndrome: case report and review.

This paper reports on a 36-year-old woman with GAPO syndrome, a rare autosomal recessive condition characterized by growth retardation (G), alopecia (A), pseudoanodontia (P), and optic atrophy (O). Her parents are consanguineous and one of her sisters is also affected. Since the first description by Anderson and Pindborg in 1947, 27 individuals have been reported with this diagnosis. They were from at least 19 different families (four of them from Brazil, including the present one), suggesting a founder effect. The phenotype of this condition, initially considered as the result of an ectodermal dysplasia, could be attributed to the accumulation of extracellular connective tissue matrix and its progressive character must be pointed out. The clinical findings, especially ophthalmological features that include bilateral glaucoma, are reviewed and discussed.

Genética molecular em atrofia óptica autossômica dominante, tipo Kjer / Molecular genetic of autosomal dominant optic atrophy, Kjer type

A atrofia óptica autossômica dominante, tipo Kjer ou juvenil, (MCKUSICK 1994; OMIM #l65500, OPAL) é uma neuropatia óptica hereditária que causa perda de acuidade visual, anormalidades da visão de cores e defeitos do campo visual, caracterizada por palidez do disco óptico. O gene desta doença foi mapeado por análise de ligação genética em um intervalo de 1O cM no cromossomo 3q28-qter (EIBERG et al., 1994). Posteriormente o intervalo de ligação da doença foi refinado para 1,4 cM entre os mercadores microssatélites D3S 3669 e D3S3562 (JONASDOTTIR et ai., 1997). Embora a maioria das famílias estudadas tenha mostrado ligação para a região cromossômica 3q28-29 (BONNEAU et al., 1995; LUNKES et ai., 1995; BROWN et aí., 1997; JOHNSTON et ai., 1997; STOILOVA et aí., 1997; VOTRUBA et ai., 1997), recentemente uma família foi mapeada no cromossomo l8ql 2.2-12.3 (KERRISON et aí., 1999). Este trabalho analisa a ligação da atrofia óptica em três famílias com mercadores polimórficos para os cromossomos 3q28-29 e l8ql2.2-12.3 e investigar genes candidatos nestes loci. Para tanto, cinqüenta e sete indivíduos de três famílias foram submetidos a exame oftamológico e coleta de sangue. O DNA foi extraído e amplificado em reações de PCR com mercadores polimórficos para os cromossomos 3q28-29 e l8ql2.2-12.3. Nas famílias onde se observou ligação, foram investigados os genes candidatos GAP43 e MBP que se localizam nestes loci. As três famílias apresentaram padrão de herança autossômico dominante com expressividade variável e alta penetrância. Na primeira família houve suspeita da atrofia óptica mapear para o cromossomo 3q28-29, mas sem significância estatística no valor do "lod score". Na segunda família B a atrofia óptica apresentou ligação para este locus. Os eventos de recombinação nesta família localizaram o gene num intervalo de 2 cM entre os mercadores D3S3669 e D3S2305. O lod score" máximo obtido foi de 3,56 no tetha de O,OO com o marcador D3S3669. A terceira família não apresentou ligação com no cromossomo 3q28-29 e nem no cromossomo l8ql2.2. A primeira família foi analisada com marcadores para o cromosssomo 12 próximos ao gene fenilanina hidroxiladse para esclarecer se havia relaçäo entre os casos de atrofia óptica, feniletonúria e retardo mental presentes nesta família. Esta análise exclui a associaçäo entre estas doenças nesta família. O fato da terceira família näo mapear para nenhum dos dois loci já descritos levou a conclusäo de que existe ...(au)

Pitt-Rogers-Danks syndrome: further delineation.

The Pitt-Rogers-Danks syndrome is an entity characterized by proportionate short stature and low weight of prenatal onset, moderate to severe mental retardation, seizures, and typical facial changes including microcephaly, telecanthus, upward or downward slanting palpebral fissures, prominent eyes, ocular abnormalities, hypoplastic maxilla, short philtrum, and large mouth. This is the seventh reported case, and the first one in which the patient also presents with optic atrophy. Autosomal recessive inheritance has been proposed until now, however, the increased paternal age seen in this case is suggestive of a possible autosomal dominant de novo mutation.

GAPO syndrome (McKusick 23074)--a connective tissue disorder: report on two affected sibs and on the pathologic findings in the older.

GAPO syndrome was described in 12 patients from 7 families. Constant manifestations include dwarfism, alopecia, pseudoanodontia, and a peculiar, "geriatric" facial appearance. We describe the autopsy findings and all available clinical data on one deceased patient and his living affected sister, previously reported as short abstracts (Epps et al.: Cienc Cult 29(Suppl):740, 1977; Wajntal et al.: Cienc Cult 34(Suppl):705, 1982). Both had the characteristic anomalies of this syndrome but optic atrophy was absent; instead, they had glaucoma and keratoconus; hypogonadism was present in both patients. Biopsy and autopsy findings show that the GAPO syndrome is a dyshistogenetic sequence due to accumulation of extracellular material and thus should be called GAPO dysplasia. We suggest that the basic defect in this autosomal recessive disorder is possibly related to a lack of breakdown of the extracellular components, perhaps due to an enzyme deficiency involved in the metabolism of extracellular matrix.

Síndrome de Behr: forma complicada de atrofia óptica hereditaria / Behr's syndrome: complicated form of hereditary optic atrophia

Se describe una hermandad de 2 individuos quienes fueron atendidos en nuestra consulta por presenatr un cuadro de ataxia y atrofia óptica bilateral asociada a signos piramidales. Las primeras manifestaciones clínicas comenzaron alrededor del año de edad y siguieron un curso lentamente progresivo. Los casos fueron diagnosticados como afectados del Síndrome de Behr, de etiología autosómica recesiva. Se destacan las características del síndrome y se realiza un revisión bibliográfica respecto a esta muy rara entidad aún no reportada en nuestro país

Ataxia cerebelosa y atrofia óptica en el niño: síndrome de Behr / Cerebellar ataxia and optic atrophy in children: Behr's syndrome

Se presenta el estudio de una familia con un sindrome de ataxia cerebelosa y atrofia óptica, de carácter hereditario, que comprende 5 generaciones y 23 miembros, de los cuales 9 están afectados. Se hizo un estudio clínico genético, oftalmológico y neurológico. El examen oftalmológico reveló en los pacientes afectados disminución importante de la agudeza visual, debida a atrofia óptica primaria de diversos grados. El campo visual también aparece comprometido y es frecuente la asociación a nistagmus y estrabismo. Desde un punto de vista neurológico se observa ataxia progresiva de tipo cerebeloso y debilidad del músculo del esfinter vesical. El estudio genealógico nos inclina a pensar en una herencia de tipo dominante, de alta penetrancia y expresividad variable. Todos estos hallazgos son compatibles con el diagnóstico de heredoataxia y atrofia óptica familiar de Behr

[Leber's disease. Genetic study of a family]. / Doença de Leber. Estudo genetico de uma familia

In this paper it is done the genetic study of a large family that segregates the hereditary optical atrophy gene. The modality of the hereditary transmission is the sex-linked recessive form (Leber's form). Five generations were studied, with a total of 134 individuals. Thirteen are affected (12 men: 1 woman). The study of the heredogram allows the observation of the high occurrence of women carriers and the affected men with descendents (2 married men in the heredogram) exhibit normal offspring (22 individuals, being 16 men and 6 women). One affected woman carrier is also observed. Such observations are in accordance with the literature. This study allows one to conclude by the high importance of genetic counselling, considering that the normal women carriers, which occur in great number, segregate the gene to individuals who will manifest the atrophy.