Dental Pulp Stem Cell-Derived Factors Alleviate Subarachnoid Hemorrhage-Induced Neuroinflammation and Ischemic Neurological Deficits.

Aneurysmal subarachnoid hemorrhage (aSAH), characterized by the extravasation of blood into the subarachnoid space caused by an intracranial aneurysm rupture, may lead to neurocognitive impairments and permanent disability and usually carries poor outcome. Dental or gingiva-derived stem cells have been shown to contribute to immune modulation and neuroregeneration, but the underlying mechanisms are unclear. In the present study, we sought to investigate whether dental pulp stem cells (DPSCs) secrete certain factor(s) that can ameliorate the neural damage and other manifestations in a rat aSAH model. Twenty-four hours after the induction of aSAH, microthrombosis, cortical vasoconstriction, and the decrease in microcirculation and tissue oxygen pressure were detected. Intrathecal administration of DPSC-derived conditioned media (DPSC-CM) ameliorated aSAH-induced vasoconstriction, neuroinflammation, and improved the oxygenation in the injured brain. Rotarod test revealed that the aSAH-induced cognitive and motor impairments were significantly improved by this DPSC-CM administration. Cytokine array indicated the major constituent of DPSC-CM was predominantly insulin growth factor-1 (IGF-1). Immunohistochemistry staining of injured brain tissue revealed the robust increase in Iba1-positive cells that were also ameliorated by DPSC-CM administration. Antibody-mediated neutralization of IGF-1 moderately deteriorated the rescuing effect of DPSC-CM on microcirculation, Iba1-positive cells in the injured brain area, and the cognitive/motor impairments. Taken together, the DPSC-derived secretory factors showed prominent therapeutic potential for aSAH. This therapeutic efficacy may include improvement of microcirculation, alleviation of neuroinflammation, and microglial activation; partially through IGF-1-dependent mechanisms.

Novel mutations in KARS cause hypertrophic cardiomyopathy and combined mitochondrial respiratory chain defect.

Mutations in KARS, which encodes for both mitochondrial and cytoplasmic lysyl-tRNA synthetase, have been so far associated with three different phenotypes: the recessive form of Charcot-Mary-Tooth polyneuropathy, the autosomal recessive nonsyndromic hearing loss and the last recently described condition related to congenital visual impairment and progressive microcephaly. Here we report the case of a 14-year-old girl with severe cardiomyopathy associated to mild psychomotor delay and mild myopathy; moreover, a diffuse reduction of cytochrome C oxidase (COX, complex IV) and a combined enzymatic defect of complex I (CI) and complex IV (CIV) was evident in muscle biopsy. Using the TruSight One sequencing panel we identified two novel mutations in KARS. Both mutations, never reported previously, occur in a highly conserved region of the catalytic domain and displayed a dramatic effect on KARS stability. Structural analysis confirmed the pathogenic role of the identified variants. Our findings confirm and emphasize that mt-aminoacyl-tRNA synthetases (mt-ARSs) enzymes are related to a broad clinical spectrum due to their multiple and still unknown functions.

Whole exome sequencing identifies the first STRADA point mutation in a patient with polyhydramnios, megalencephaly, and symptomatic epilepsy syndrome (PMSE).

Polyhydramnios, megalencephaly, and symptomatic epilepsy syndrome (PMSE) is an ultra rare neurodevelopmental disorder characterized by severe, infantile-onset intractable epilepsy, neurocognitive delay, macrocephaly, and craniofacial dysmorphism. The molecular diagnosis of this condition has thus far only been made in 16 Old Order Mennonite patients carrying a homozygous 7 kb founder deletion of exons 9-13 of STRADA. We performed clinical whole exome sequencing (WES) on a 4-year-old Indian male with global developmental delay, history of failure to thrive, infantile spasms, repetitive behaviors, hypotonia, low muscle mass, marked joint laxity, and dysmorphic facial features including tall forehead, long face, arched eyebrows, small chin, wide mouth, and tented upper lip. A homozygous single nucleotide duplication, c.842dupA (p.D281fs), in exon 10 of STRADA was identified. Sanger sequencing confirmed the mutation in the individual and identified both parents as carriers. In light of the molecular discoveries, the patient's clinical phenotype was considered to be a good fit for PMSE. We identified for the first time a homozygous point mutation in STRADA causing PMSE. Additional bi-allelic mutations related to PMSE thus far have not been observed in Baylor ∼6,000 consecutive clinical WES cases, supporting the rarity of this disorder. Our findings may have treatment implications for the patient since previous studies have shown rapamycin as a potential therapeutic agent for the seizures and cognitive problems in PMSE patients. © 2016 Wiley Periodicals, Inc.

Molecular characterization of microduplication 22q11.2 in a girl with hypernasal speech.

We present a 12-year-old girl with karyotype 46,XX. A comparative genomic hybridization array revealed a 3.172-Mb microduplication on 22q11.2. This chromosome 22q11.2 region microduplication has been described in patients with variable phenotypes; a large majority of them have identical 3-Mb duplications. The girl presented mild mental motor retardation, facial dysmorphism consisting of a long narrow face, widely spaced eyes, downslanting palpebral fissures, broad nasal base, short philtrum, thin upper lip, micro/retrognathia, low set and retroverted ears, microcephaly, high-arched palate, hypoplastic teeth, and hypernasal speech. She had delayed psychomotor development and behavioral problems. Molecular characterization of patients differs greatly among reports and detailed molecular characterization and documentation are needed to better understand the effects of these duplications. This description of the phenotype of a patient with microduplication on 22q11.2 will contribute to the growing knowledge regarding deletions and duplications of the 22q11.2 region; this is important to conclude whether 22q11.2 duplication is a microduplication syndrome or not.

Interstitial deletion of 18q: comparative genomic hybridization array analysis of 46, XX,del(18)(q21.2.q21.33).

BACKGROUND: Interstitial deletion of chromosome 18q is rare, making it difficult to assign phenotypes to particular cytogenetic deletions. CASE: We present an 18-year-old female with an interstitial deletion of chromosome 18q21.2-q21.33. The clinical features included severe psychomotor retardation with mild growth retardation, hypotonia, midfacial hypoplasia, carp-shaped mouth, hypertelorism, strabismus, narrow upward slant palpebral fissures, short philtrum, everted lower lip, malformed ears, flat nasal bridge, and epicanthic folds. Brain abnormalities, such as agenesis of the corpus callosum, and abnormalities of the hands and feet were absent. Initially, the deletion was recognized as 18q21.1-q21.31 by conventional chromosomal analysis, and microarray-based comparative genomic hybridization revealed a 9.6-Mb deletion at 18q21.2-q21.33. The deletion included the transcription factor 4 gene and the methyl-CpG binding domain protein 2 (MBD2) gene, but not the MBD1 gene. CONCLUSIONS: The deletion of the transcription factor 4 gene suggested a possible contribution of the deletion to the patient's facial abnormalities, as observed in Pitt-Hopkins syndrome. Together with other reported cases with interstitial deletion of 18q, a possible contribution of haploinsufficiency in both MBD1 and MBD2 genes to a Rett syndrome-like phenotype was suggested, but further genetic studies on other cases are necessary to clarify the genotype-phenotype correlation.

One-month-old girl presenting with pseudohypoaldosteronism leading to the diagnosis of CDK13-related disorder: a case report and review of the literature.

BACKGROUND: It is not uncommon that an infant with a disease of unknown etiology is presented to a physician. Facial dysmorphic features lead to a different diagnosis. It is a challenge to link the presentation to the newfound diagnosis. CASE PRESENTATION: A 37-day-old Yemenite Jewish girl was presented to our institution with a clinical picture of pseudohypoaldosteronism due to abnormal facial features and a psychomotor developmental delay. Further investigation led to the diagnosis of CDK13-related disorder. According to the literature, CDK13 has a key role in the cell cycle, but no interference with the aldosterone signaling pathway or electrolyte balance was described. No mutations in the previously described gene NR3C2 (cytogenetic location 4q31.23), encoding the mineralocorticoid receptor, were found. Although the clinical presentation corresponded to pseudohypoaldosteronism type 1, we could not genetically confirm this. CONCLUSIONS: Probably pseudohypoaldosteronism was a coincidental finding in this girl with a CDK13 mutation, but because only limited information is known about CDK13-related disorders, further investigation could be more informative to clarify this presentation.

[Intraoperative and postoperative analgesia with a caudal catheter in a child suffering from Schwartz-Jampel syndrome]. / Intra- und postoperative Analgesie mit Kaudalkatheter bei einem Kind mit Schwartz-Jampel-Syndrom.

The Schwartz-Jampel syndrome, also known as myotonia chondrodystrophica, is a rare autosomal recessive disorder characterized by bone dysplasia, growth retardation and generalized myotonia. Laryngoscopy and intubation may be difficult because of micrognathia and limited mouth opening due to myotonia of the masseter muscles. As regional anaesthesia reduces myotonic contractions and avoids administration of opioids causing respiratory depression, it appears to be the ideal method for postoperative analgesia. We report on a 5-year-old girl who underwent osteotomy of both hips and received intraoperative and postoperative analgesia via a caudal catheter. Excellent analgesia without myoclonic episodes could be achieved by continuous infusion of ropivacaine.

Knockdown of the Drosophila FIG4 induces deficient locomotive behavior, shortening of motor neuron, axonal targeting aberration, reduction of life span and defects in eye development.

Mutations in Factor-Induced-Gene 4 (FIG4) gene have been identified in Charcot-Marie-Tooth disease type 4J (CMT4J), Yunis-Varon syndrome and epilepsy with polymicrogyria. FIG4 protein regulates a cellular abundance of phosphatidylinositol 3,5-bisphosphate (PI(3,5)P2), a signaling lipid on the cytosolic surface of membranes of the late endosomal compartment. PI(3,5)P2 is required for retrograde membrane trafficking from lysosomal and late endosomal compartments to the Golgi. However, it is still unknown how the neurodegeneration that occurs in these diseases is related to the loss of FIG4 function. Drosophila has CG17840 (dFIG4) as a human FIG4 homolog. Here we specifically knocked down dFIG4 in various tissues, and investigated their phenotypes. Neuron-specific knockdown of dFIG4 resulted in axonal targeting aberrations of photoreceptor neurons, shortened presynaptic terminals of motor neurons in 3rd instar larvae and reduced climbing ability in adulthood and life span. Fat body-specific knockdown of dFIG4 resulted in enlarged lysosomes in cells that were detected by staining with LysoTracker. In addition, eye imaginal disk-specific knockdown of dFIG4 disrupted differentiation of pupal ommatidial cell types, such as cone cells and pigment cells, suggesting an additional role of dFIG4 during eye development.

Further delineation of the KAT6B molecular and phenotypic spectrum.

KAT6B sequence variants have been identified previously in both patients with the Say-Barber-Biesecker type of blepharophimosis mental retardation syndromes (SBBS) and in the more severe genitopatellar syndrome (GPS). We report on the findings in a previously unreported group of 57 individuals with suggestive features of SBBS or GPS. Likely causative variants have been identified in 34/57 patients and were commonly located in the terminal exons of KAT6B. Of those where parental samples could be tested, all occurred de novo. Thirty out of thirty-four had truncating variants, one had a missense variant and the remaining three had the same synonymous change predicted to affect splicing. Variants in GPS tended to occur more proximally to those in SBBS patients, and genotype/phenotype analysis demonstrated significant clinical overlap between SBBS and GPS. The de novo synonymous change seen in three patients with features of SBBS occurred more proximally in exon 16. Statistical analysis of clinical features demonstrated that KAT6B variant-positive patients were more likely to display hypotonia, feeding difficulties, long thumbs/great toes and dental, thyroid and patella abnormalities than KAT6B variant-negative patients. The few reported patients with KAT6B haploinsufficiency had a much milder phenotype, though with some features overlapping those of SBBS. We report the findings in a previously unreported patient with a deletion of the KAT6B gene to further delineate the haploinsufficiency phenotype. The molecular mechanisms giving rise to the SBBS and GPS phenotypes are discussed.

Lower lip pits and complete idiopathic precocious puberty in a patient with Kabuki make-up (Niikawa-Kuroki) syndrome.

We report on a 13 1/2-year-old patient with Kabuki make-up syndrome and complete idiopathic precocious puberty manifested at 7 1/2 years. In addition to the other specific clinical signs, she showed hypodontia and lower lip pits, as typically seen in the Van der Woude syndrome. The significance of lower lip pits in the Kabuki make-up syndrome is discussed.

Ectomorphic habitus, severe mental retardation and characteristic face: a new MCA/MR syndrome?

Here we report on 2 mentally retarded sisters with clinical signs and symptoms not seen in a previously delineated MCA/MR syndrome, i.e., normal pre- and perinatal history, severe mental retardation with severe delay in psychomotor development and without development of primary motor abilities and speech, characteristic face with maxillary hypoplasia, large mouth with down-turned corners, short philtrum and everted lower lip, associated with a remarkable ectomorphic habitus.

Unbalanced 4;6 translocation and progressive renal disease.

Two sibs are described with an unbalanced 4;6 translocation resulting in partial trisomy 6p and monosomy for distal 4p. Growth retardation, psychomotor retardation, and characteristic facial appearance are present. The facial anomalies include high prominent forehead, blepharoptosis, blepharophimosis, high nasal bridge, bulbous nose, long philtrum, small mouth with thin lips, and low-set ears. Both children have small kidneys and have had proteinuria since early childhood. The older boy developed progressive renal disease including hypertension and renal failure necessitating renal transplantation at age 18 years. Renal biopsy of the younger girl also indicates significant renal involvement. Progressive renal disease is likely an important part of the trisomy 6p phenotype.

Child with Sotos phenotype and a 5:15 translocation.

We report on a 4-year-old girl with Sotos phenotype and a de novo balanced translocation between the long arms of chromosome 5 and chromosome 15 [46,XX,t(5,15)(q35;q22)]. We suggest a relationship between genetic material at 5q35 or 15q22 and the expression of an autosomal dominant gene.

[Trichothiodystrophy: progresssive manifestations]. / Trichothiodystrophies: manifestations évolutives.

INTRODUCTION: Trichothiodystrophy is an autosomal recessive genodermatosis associating congenital dysplasia of the hair and neuroectodermal defects. Clinical expression is variable, although abnormalities are generally noted from birth. We report trichothiodystrophy in two brothers with the same phenotype who presented unusual progressive manifestations. OBSERVATIONS: Case 1: A six-year-old boy was seen for vesicular blisters due to photosensitization. Clinical examination showed dry, brittle, unmanageable hair, discrete koilonychia-type nail defects and an ichthyosiform state. The teeth were normal. In addition to psychomotor retardation, the patient presented a dysmorphic syndrome (poorly rimmed low-set ears; thick, triangular upper lip; scaphocephalic skull; short hands) and congenital bilateral cataract. The diagnosis of trichothiodystrophy was confirmed by a study of DNA repair after exposure to ultraviolet light. A repair defect was found similar to that in xeroderma pigmentosum group D. The patient experienced a worsening of psychomotor retardation and episodes of hair loss with edema and inflammation of the scalp resulting from infections. He also showed marked asthenia which resolved spontaneously within a few months. Case 2: The other brother, born as a collodion baby, presented the same clinical picture (cutaneous, exoskeletal, dysmorphic), including congenital bilateral cataract, photosensitivity and a parenchymatous blister-type pulmonary lesion probably secondary to bronchiectasis. The patient's cutaneous state progressively improved. He was seen at six years of age for an episode of inflammatory edema of the scalp with hair loss. Within six months, all of the hair redrew. The diagnosis of trichothiodystrophy was confirmed by a DNA repair defect after exposure to ultraviolet light. DISCUSSION: Trichothiodystrophy is clinically associated with photosensitivity (P), ichthyosis (I), dry, brittle hair (B), intellectual impairment (I), decreased fertility (D) and short stature (S), which accounts for the acronym PIBIDS or IBIDS syndrome, depending on whether photosensitivity is involved or not (actually in about 50 p. 100 of cases). Other possibly associated features include ungueal dysplasias, bilateral cataract, defective teeth, dysmorphic disorders predominant in the ears, neurologic disorders, pulmonary bronchiectasis and recurrent infections. The two cases presented here were thus very symptomatologically complete. The two problems of current concern are psychomotor retardation and temporary hair loss as a result of infections. The latter has only been described once in the literature. This case was similar to ours since photosensitivity was involved. Analysis of DNA repair also showed a defect after exposure to ultraviolet light similar to that found in xeroderma pigmentosum group D. Thus, episodic hair loss could be a symptom characteristic of forms of trichothiodystrophy with a DNA repair defect. However, the explanation for this hair loss is not known. Other ectodermal dysplasias can be complicated by hair loss with superinfection, such as AEC syndrome (ankyloblepharon, ectodermal dysplasia, cleft palate).

[Partial trisomy for the long arm of chromosome 2 due to malsegregation of a maternal insertion : ins(6;2)(p22;q24q34)]. / Trisomie partielle pour le bras long du chromosome 2 par malségrégation d'une insertion maternelle : ins(6;2)(p22;q24q34).

A 6p+ chromosome was observed in a dysmorphic and mentally retarded child. The mother was found to be carrier of an insertion: ins(6;2) (p22;q24;q34). The patient was therefore trisomic for 2q24 leads to 2q34. The same insertion was found in his brother in the balanced state. A comparison of this observation and four other cases from the literature allows a description of the symptoms characteristic of trisomy 2q24 leads to 2q34 : mid-face hypoplasia, carp-shaped mouth, neurological disorders, severe mental retardation.

Partial trisomy 6p.

A case of trisomy 6p21 leads to 6pter resulting from a maternal balanced t(2;6)(p25;p21) translocation is reported. The main clinical abnormalities were psychomotor retardation, hypotrophy, blepharophimosis, nystagmus, high nasal bridge, small mouth, sacral dimple, and systolic murmur. Other anomalies might have been due to partial 2p monosomy. Comparison with seven other cases of trisomy 6p allowed the delineation of a clinical entity. Direct proof of the localization of HLA genes was given by the presence of three haplotypes in the index patient.

Trisomy of the distal third of the long arm of chromosome 10. Report of a new case due to a familial translocation t(10;18) (q24;p11).

A new case of trisomy of the distal third of the long arm of chromosome 10 due to familial translocation t(10;18) (q24;p11) is described. The main clinical and radiological signs may be summarized as follows: growth at lower limits of normal; poor facial expression; round, flat face with high, broad forehead, fine, highly arched eyebrows, pseudohyperthelorism, microphthalmia, flat, broad bridged nose, hypoplasia of the bony structures of the central area of the face, "fish mouth", macroglossia, micrognathia; short neck; marked dextroconvex lumbar scoliosis; psychomotor delay of mild degree; selective, more pronounced speech delay. Our observation confirms the suggestion by Yunis and Sanchez that a clinical syndrome corresponds to this chromosomal alteration. However, some interesting differences from the previously reported cases, i.e., the absence of microcephaly and of severe impairment of growth and psychomotor development induce us to establish a more favorable prognosis in our case.

Partial trisomy 12q24.31----qter.

Clinical details of a male child with the karyotype 46,XY,-4,+der(4),t(4;12) (p16;q24.31)mat are reported and compared with those of other known cases of partial trisomy of the distal region of 12q. This condition is apparently associated with mental and psychomotor retardation, widely spaced eyes, flat nasal bridge, low set ears, down-turned mouth, micrognathia, loose skin at the nape, widely spaced nipples, simian creases, clinodactyly, abnormalities of the genitourinary system, alterations in the sacrococcygeal region, and deformities of the lower limbs. In the majority of the reported cases, the break-point was in the 12q24 region and resulted from adjacent 1 segregation of a maternal balanced translocation.

Duplication 9q34 syndrome.

Phenotypic, karyotypic, and developmental homology between affected children of carriers of an inverted insertion (9) (q22.1q34.3q34.1) led to recognition of a new chromosome syndrome: dup 9q34. Individuals with dup 9q34 have slight psychomotor retardation, understand simple directions, and acquire a limited vocabulary. In childhood, many are hyperactive. Clinical features include low birth weight, normal birth length, and initial poor feeding and thriving. Musculo-skeletal systems are affected: there are joint contractures, long thin limbs, and striking arachnodactyly. There is abnormal implantation of the thumb, increased space between the first and second fingers, and excess digital creases. Marfan syndrome was a provisional diagnosis for several cases prior to cytogenetic analysis. Cardiovascular and ocular systems are minimally affected, erythema and heart murmurs occur, and ptosis and strabismus are frequent, but lens dislocation is not observed. Features at birth include: dolichocephaly, facial asymmetry, narrow horizontal palpebral fissures, microphthalmia, prominent nasal bridge, small mouth, thin upper lip with down-turned corners, and slight retrognathia. In older children, retrognathia is diminished and the nose becomes long and narrow. The new culture and chromosome banding techniques enable sorting of cases with the distal dup 9q phenotype into two groups. The cases with a longer dup 9q are more likely to develop with life-threatening congenital anomalies. The cases with the shorter dup 9q34 have a less severe long-term prognosis and will benefit, together with their parents, from special education. Female carriers of the inv ins(9) (q22.1q34.3q34.1) have about a 31% risk in each pregnancy to conceive a fetus affected by the dup 9q34 syndrome. A comparable figure is not yet available for male carriers.

[Partial trisomy 14q II.--Partial trisomy 14q due to a maternal t(12; 14) (q24.4; q21)]. / Trisomie 14q partielle. II.--Trisomie 14q partielle par translocation maternelle t(12; 14) (q24.4; q21)

The phenotype of an 18-month-old male infant trisomic for the proximal portion of the long arm of chromosome 14 was reported and compared with that of previously reported cases. For the identification of the resulting syndrome, the most consistent features are psychomotor and growth retardation, and an oval, dysmorphic facies which includes a distinctive form of the mouth and a prominent nose. The trisomy in the child reported here is due to a familial translocation transmitted by the mother and present in at least three generations: t(12;14)(q24.4;q21). The 12q duplication in the child's genome is minimal and does not seem to have contributed to his phenotype.