Kearns-Sayre syndrome with facial and white matter extensive involvement: a (mitochondrial and nuclear gene related?) neurocristopathy?

The Authors report on a patient with Kearns-Sayre syndrome, large mtDNA deletion (7/kb), facial abnormalities and severe central nervous system (CNS) white matter radiological features, commonly attributed to spongy alterations. The common origin from neural crest cell (NCC) of facial structures (cartilagineous, osseous, vascular and of the peripheral nervous system) and of peripheral glia and partially of the CNS white matter are underlined and the facial and glial abnormalities are attributed to the abnormal reproduction/migration of NCC. In this view, the CNS spongy alterations in KSS may be not only a dystrophic process (leukodystrophy) but also a dysplastic condition (leukodysplasia).

Oculo-auriculo-vertebral spectrum with myopathy and velopharyngeal insufficiency. A case report with a non-branchiomeric muscle biopsy.

In the present paper we report on a case of oculo-auriculo-vertebral spectrum presenting fluorescence in situ hybridization and comparative genomic hybridization tests negative, hypotonia of some branchiomeric muscles (with velo-pharyngeal insufficiency, dysphagia and nasal voice) and non-branchiomeric muscles (with strabismus and limb hypotrophy). On the basis of the left quadriceps muscle biopsy, showing anisometry and prevalence of type 1 fibers, and on literature data, we underline the relevance of TBX1 gene (regulator of neural crest cells and activator of myogenic factors in branchiomeric muscles development) and of PAX3 gene (present in neural crest, inducing migration of these cells and reported in non-branchiomeric muscles). We conclude that the case of OAVS presented a generalized myopathy and we hypothesize that a cluster of genes strictly neural crest cells related, including TBX1 and PAX3, may be responsible of the branchiomeric and non-branchiomeric myopathy; alternatively, a regulatory mechanism abnormally common to OAVS and velo-cardio-facial syndrome could be present.

Oculo-auriculo-vertebral spectrum with craniosynostosis and osteo-cartilagineous multiple defects: a diffuse chondro-membranous-osteo-dysplasia.

We report on a female with oculo-auriculo-vertebral spectrum, low height, and on X-ray lambdoid suture synostosis, cerebral cyst/mild holoprosencephalia and cholesteatoma, and multiple abnormalities of bones of chondral origin. On the right side, maxillary, mandibular bones, external auditory canal, middle ear were hypoplastic as well as semicircular canal, cranial base, bones vestibule. On the left side, coclea, timpanic cavity, mastoid antrum were hypoplastic, while stapes was misshapen.

Activity of drugs and components of natural origin in the severe myoclonic epilepsy of infancy (Dravet syndrome).

The sea anemones (Cnidaria) produce neurotoxins, polypeptides active on voltage-gated sodium channels, which induce a non-inactivating condition, with consequent seizures and paralysis in zebrafish (Danio rerio). In humans, severe myoclonic epilepsy of infancy (SMEI) is due to SCN1A gene mutation, which causes a non-inactivating sodium channels condition with seizures. Some symptoms, such as age of first seizure, repetitive events, frequent status epilepticus, scarce responsiveness to antiepileptic drugs (AEDs), may be due to superimposed environmental causes.

Association of severe myoclonic epilepsy of infancy (SMEI) with probable autoimmune lymphoproliferative syndrome-variant.

The paper reported on a case of severe myoclonic epilepsy of infancy (SMEI) associated with a probable autoimmune lymphoproliferative syndrome variant (Dianzani autoimmune lymphoproliferative disease) (DALD). A male patient with typical features of SMEI and a SCN1A gene variant presented in the first year of life with multiple lymph nodes, palpable liver at 2 cm from the costal margin, neutropenia, dysgammaglobulinemia, relative and sometimes absolute lymphocytosis. Subsequently the patient presented with constantly raised IgA in serum and positive antinuclear and thyroid antimicrosomal antibodies.

Precocious puberty in a patient with Oculo-Auriculo-Verebral spectrum (OAVS).

The authors report on the first case of OAVS (Oculo-Auriculo- Vertebral-Spectrum), with hemifacial microsomy, hydrocephalus, pubertas precox, thelarche at 4 years of age, vaginal bleeding at 5 years, and left ovary of adult type on echography (right ovary initially not visualized). FISH and CGH-ARRAYS methods were negative. By GnRH therapy the delay of onset puberty was obtained.

Multiple endocrinopathies (growth hormone deficiency, autoimmune hypothyroidism and diabetes mellitus) in Kearns-Sayre syndrome.

Kearns-Sayre syndrome is characterized by onset before 20 years, chronic progressive external opthalmoplegia, pigmentary retinal degeneration, and ataxia (and/or hearth block, and/or high protein content in the cerebrospinal fluid) in the presence of mtDNA rearrangements. Multiple endocrine dysfunction associated with this syndrome was rarely reported. In this paper, the Authors report on a female patient with Kearns-Sayre syndrome with large heteroplasmic mtDNA deletion, absence of cytochrome c oxidase in many muscle fibers, partial GH deficiency, hypothyroidism and subsequently insulin dependent diabetes mellitus (IDDM).

[Arachnoid cyst, hypoplasic temporal lobe and facial anomalies: a neurocristopathy].

The authors report on a patient which presented at birth facial anomalies similar to those of facial alcoholic syndrome (i.e. high forehead, wide nasal bridge, upturned nose, flat philtrum), low set ears, short neck.

[Serious cerebral malformations (corpus callosum aplasia, prosencephalic cyst), internal carotid canal and facial malformations due to neural crest abnormalities, associated with choleosteatoma].

The authors report an original case of malformative spectrum, which includes cerebral (corpus callosum aplasia, prosencephalic cyst) facial, otic and basi-cranial dysplasias associated with cholesteatoma. Cephalic neural crest cells migrate to different regions in the head and neck, where they contribute to the development of mainly the first and second branchial arches and of many structures as the anterior skull base, the face, the ear and the forebrain. Data suggest that the link between these rare malformations is abnormal neural crest development, perhaps due to defective Hh signal.

[Leigh syndrome with facial abnormalities: a neurocristopathy].

A case of Leigh syndrome with respiratory chain defect and facial abnormalities is reported. Because most of the facial skeleton originates from the neural crests, which are strictly connected with the Central Nervous System development, the authors speculate that the facial abnormalities, observed in Leigh syndrome, are dependent on neural crest development disturbances (dysneurulation) and related to neurological features and that Leigh syndrome is a neurocristopathy. In case of facial abnormalities in infancy Leigh syndrome with respiratory chain defect should be investigated.

Facial anomalies in a patient with cytochrome-oxidase deficiency and subsequent Kearns-Sayre syndrome with growth hormone deficiency.

The authors report on a patient with mild cranio-facial abnormalities observed at birth and growth hormone deficiency, which later developed a typical Kearns-Sayre syndrome. Facial abnormalities are similar to those reported in the fetal alcohol syndrome (a typical neural crest syndrome). In the authors' opinion, they could be an abnormality of neural crest cell development or migration, due to expression of antenatal oxidative phosphorylation deficiency in neural crest cells or to an interference of defective oxidative phosphorylation with neural crest cells signal(s).

A case of Kearns-Sayre sindrome with autoimmune thyroiditis and complete atrio-ventricular block.

The Kearns-Sayre syndrome, (characterized by its onset before the age of 20 years, chronic ophthalmoplegia, pigmentary retinal degeneration and at least one of the following symptoms: ataxia, heart block and high protein content in the cerebrospinal fluid) is a severe variant of chronic progressive external ophthalmoplegia with frequent rearrangements of the mitochondrial DNA (mtDNA). The aim of this paper is to report a sporadic paediatric case of Kearns-Sayre syndrome with mtDNA heteroplasmic deletion, absence of cytochrome c-oxidase in many muscle fibers, autoimmune thyroiditis, complete atrio-ventricular heart block in which the diagnosis of subclinical hypothyroiditis associated with autoimmune thyroid disease was made. The subclinical hypothyroidism, more severe in the presence of thyroid antibodies, may have contributed to the pathogenesis of cardiovascular disease.

Enhanced biofilm-production in pathogens isolated from patients with rare metabolic disorders.

Biofilm-producing bacteria were isolated from the urine of 19 patients with very rare metabolic disorders including: hyperlactacidaemia (8 cases), sugar intolerance and gammopathy (1 case), cystinuria (2 cases), Parkinson's disease (1 case), lipidaemia (2 cases), hyperaminoaciduria (1 case) and others (4 cases). A total of 34 strains were collected, Gram-negative and gram-positive microorganisms were equally distributed among the slime-producing bacteria, with a prevalence of Staphylococcus epidermidis (30%) the most frequent microorganism isolated together with Escherichia coli and Proteus mirabilis that accounted for 15% of this group of strains. A quantitative assay of the biofilm production revealed that in Gram-positive pathogens it was three times greater than that observed in bacteria collected from patients not affected by metabolic diseases (p = 0.

Facial anomalies in patients with cytochrome-c-oxidase (COX) deficiency: a dysneurulation.

The authors report 3 cases of cytochrome-c-oxidase deficiency (2 cases of Kearns-Sayre syndrome and 1 case of chronic progressive external ophthalmoplegia) with Central Nervous System alterations and facial anomalies. The facial anomalies are high forehead, wide nasal bridge, upturned nose, long and flat philtrum (alterations depending on frontal-nasal-premaxillary structures which derive from prosencephalic neural crests), hypoplastic maxilla and mandible, ophthalmoplegia (alterations of maxilla and III-VI cranial nerve nuclei, which derive on the mesencefalic neural crests), low set ears, short neck (alterations of the 3rd, 4th branchial arch derivatives, which arise from rhombencephalic neural crests). The authors conclude that cytochrome-c-oxidase deficiency in embryonic stage can injure, in Kearns-Sayre syndrome and chronic progressive external ophthalmoplegia, distal tissues of face and Central Nervous System depending on neural crests, and that the symptomatology of these diseases can be ascribed to dysneurulation.

[Kearns-Sayre syndrome associated with growth hormone deficiency].

The Authors report a 10 years old boy with Kearns-Sayre syndrome and growth hormone (GH) deficiency. The patient was treated with human recombinant GH for 6 months but the growth velocity/year did not change. The Authors report a brief review of the literature on the ethiopatogenesis of GH deficiency observed in this patient is given.

[Stickler syndrome: maxillo-facial abnormalities].

A case of Stickler syndrome (hereditary arthro-ophthalmo-dystrophy) with maxillo-facial abnormalities and colon atresia is reported. The authors emphasize that in Stickler syndrome, (a chondrodystrophy with congenital alteration of type II collagen) the maxillofacial abnormalities are consecutive to prosencephalic neural crests dysneurulation, which caused mesethmoidal dysneurulation (and consequently of frontonasal-premaxillary structures); eye and colon abnormalities are consecutive to rhombo-mesencephalic neural crests dysneurulation. The Authors hypothesize that genic mutation, responsible of enzymatic deficiency of the neural crest multipotent cells, caused a morphogenetic alteration of the fronto-naso-philtral structures of the midface and of low face structures.

[Maxillo-facial abnormalities in Kearns-Sayre syndrome].

Three cases of Kearns-Sayre Syndrome are reported, in which some facial anomalies, including facial asymmetry, high forehead, wide nasal bridge, upturned nose, flat philtrum, low set ears and short neck were present. In two cases, the diagnosis of oxidative phosphorylation deficiency was confirmed by hystoenzymatic and genetic studies. The relationship of these facial anomalies with neural crest maldevelopment is emphasized and a classification of the Kearns-Sayre Syndrome as metabolic neurocristopathy is proposed.

A case of Kearns-Sayre syndrome with autoimmune thyroiditis and possible Hashimoto encephalopathy.

The Kearns-Sayre syndrome (characterized by onset before 20, chronic ophthalmoplegia, pigmentary retinal degeneration and at least 1 of the following symptoms: ataxia, heart block and high protein content in the cerebrospinal fluid) is a severe variant of chronic progressive external ophthalmoplegia (CPEO) with frequent re-arrangements of the mitochondrial DNA (mtDNA). The aim of this paper is to report a sporadic paediatric case of Kearns-Sayre syndrome with mtDNA heteroplasmic deletion, absence of cytochrome c oxidase in many muscle fibers, autoimmune thyroiditis followed by depressive phobic disturbances, slowing EEG, hyperreflexia, tremor and visual hallucinations, in which the diagnosis of possible encephalopathy associated with autoimmune thyroid disease (Hashimoto encephalopathy) was made. We speculated that in this patient, predisposed by mitochondrial deletion, anti-thyroid antibodies may have interfered with mitochondrial cerebral function, causing Hashimoto encephalopathy and facilitating ophthalmoplegia.