Reading impairment after neonatal hypoglycemia with parieto-temporo-occipital injury without cortical blindness: A case report.

BACKGROUND: Perinatal brain injury may lead to later neurodevelopmental disorders, whose outcomes may vary due to neuroplasticity in young children. Recent neuroimaging studies have shown that the left parietotemporal area (which includes the left inferior parietal lobe) is associated with phonological awareness and decoding skills, which are essential skills for reading acquisition in children. However, the literature on the effect of perinatal cerebral injury on the development of phonological awareness or decoding ability in childhood is limited. CASE SUMMARY: We report the case of an 8-year-old boy who presented with reading difficulty following a perinatal injury in the parieto-temporal-occipital lobes. The patient was born at term and was treated for hypoglycemia and seizures during the neonatal period. Diffusion-weighted brain magnetic resonance imaging on postnatal day 4 revealed cortical and subcortical hyperintensities in the parieto-temporo-occipital lobe. At the age of 8 years, physical examination was unremarkable, aside from mild clumsiness. Despite occipital lobe injury, the patient had adequate visual acuity, normal eye movement, and no visual field defects. Full-scale intelligence quotient and verbal comprehension index on Wechsler Intelligence Scale for Children-Fourth Edition were 75 and 90, respectively. Further assessment revealed adequate recognition of Japanese Hiragana letters. However, he had significantly slower reading speed in the Hiragana reading test than control children. The phonological awareness test revealed significant errors (standard deviation +2.7) in the mora reversal task. CONCLUSION: Patients with perinatal brain injuries in the parietotemporal area require attention and may benefit from additional reading instructions.

Death review of children receiving medical care at home.

BACKGROUND: Children receiving home medical care need special attention to prevent unexpected death. The aim of this study was to clarify the factors contributing to death in children receiving home medical care from the child death review database. METHODS: Children receiving home medical care were enrolled from the child death review database from 2014 to 2016 in Aichi prefecture, Japan, with a population of one million children. Types of medical care and factors contributing to death were examined. RESULTS: Of the 631 children who died, 40 children (6%) were receiving home medical care (21: tracheostomy; 19: ventilator; 26: suctioning of naso-oral secretions; 19: oxygen inhalation; 32: tube feeding; 6: urethral catheterization; and 1: peritoneal dialysis). The death rate was 50 times that in the general population of children. Ten children had contributory factors that seemed to be preventable. In four children, the families could not replace the tracheostomy tubes during an accident. In three, oxygen saturation or ventilator alarms were not set appropriately. In two, an oxygen cylinder became empty. One child fell down from a seat in a car. CONCLUSIONS: Improvement of devices and correct guidance to caregivers may reduce the death rate in children receiving home medical care. IMPACT: Children receiving home medical care, such as tracheostomy care, mechanical ventilation, or tube feeding, need special attention to prevent unexpected death. In this population-based child death review, 6% of children received home medical care, and it was estimated that 1 of 100 children receiving home medical care died per year. One-quarter of the deaths could be preventable by caregiver education or development of devices.

Shuffling babies and autism spectrum disorder.

BACKGROUND AND PURPOSE: Bottom shuffling is a locomotion strategy that precedes independent walking in some infants. Shuffling babies are generally considered to have favorable outcomes. The aim of the present study was to reveal clinical features and neurodevelopmental outcomes of shuffling babies who visited a child developmental center. METHODS: We studied 48 shuffling babies who visited Toyota Municipal Child Development Center from April 2007 to March 2015. We excluded patients with cerebral palsy, Down syndrome, or congenital disorders. In 2018, we retrospectively reviewed the clinical charts of the enrolled children. We investigated family history, neurological findings, and the developmental outcome during the follow-up period. RESULTS: During the follow-up period, 20 children (42%) were diagnosed with ASD. Gross motor development in infancy was not different between infants with and without ASD. The rate of poor eye contact at the first visit and a delay in the first word speech were significantly higher in infants with ASD than in infants without ASD. A family history of bottom shuffling was significantly less frequent in infants with ASD (10%) than in those without (39%). CONCLUSION: Some of bottom shufflers may represent ASD during follow-up. Paying attention to social and cognitive functions in shuffling babies is important.

Establishing SON in 21q22.11 as a cause a new syndromic form of intellectual disability: Possible contribution to Braddock-Carey syndrome phenotype.

A recent study of exome analyses in 109 patients with undiagnosed diseases included a 5-year-old girl with intellectual disability and multiple congenital anomalies, who had an apparently de novo frameshift mutation in SON. However, the combination of the truncating mutation in SON and the phenotype has not been reproduced until date, and it remains unclear if this combination represents a distinctive disease entity. Here we report an additional male with intellectual disability, congenital heart disease, distinctive facial features with curly hair and protruding ears, and long slender extremities, and hyperextensible joints. Exome analysis showed that he had the same de novo frameshift mutation in SON in a heterozygous state. Along with the first and original description of the apparently de novo truncating mutation in SON mentioned above, we have established that haploinsufficiency of SON causes a new recognizable syndrome of intellectual disability. SON is located within 21q22.11, a critical region for Braddock-Carey syndrome, which is characterized by congenital thrombocytopenia, intellectual disability, micrognathia, and a distinctive facies. Therefore, we suggest that the intellectual disability observed in Braddock-Carey syndrome could be accounted for by haploinsufficiency of SON. © 2016 Wiley Periodicals, Inc.

[The rewards of working with medicine for patients with severe motor and intellectual disabilities].

I think that medicine for patients with severe motor and intellectual disabilities (SMID) should aim to help them and their families to promote a better quality of life in their communities by building multidisciplinary networks. Below, I mention four personal opinions on why I find working with medicine for SMID patients attractive: 1. Sharing in the joy experienced by SMID patients and their family members as they learn to cope with SMID and grow as people. When I see how patients who are affected by SMID and their family members grow and lead fulfilling lives, I feel that my work has been richly rewarded. 2. The joy of being considered reliable and appreciated. I feel highly rewarded when I earn the trust of the family members, and I get a word of gratitude from them. 3. Enjoying the experience of working with ingenious and team medicine. I experience a feeling of accomplishment after engaging in intense discussions on successful preventive innominate transections. 4. The opportunity to make a social contribution. I believe that I can contribute to making our world more livable to a greater number of people. To spread awareness about the attractiveness of SMID medicine, I provide SMID medicine education at Nagoya University. My lectures and training are attended by patients with SMID and their families. I also hope that many young doctors become interested in SMID medicine and find it an enjoyable experience.

Seizure characteristics of epilepsy in childhood after acute encephalopathy with biphasic seizures and late reduced diffusion.

OBJECTIVE: The aim of this study was to clarify characteristics of post-encephalopathic epilepsy (PEE) in children after acute encephalopathy with biphasic seizures and late reduced diffusion (AESD), paying particular attention to precise diagnosis of seizure types. METHODS: Among 262 children with acute encephalopathy/encephalitis registered in a database of the Tokai Pediatric Neurology Society between 2005 and 2012, 44 were diagnosed with AESD according to the clinical course and magnetic resonance imaging (MRI) findings and were included in this study. Medical records were reviewed to investigate clinical data, MRI findings, neurologic outcomes, and presence or absence of PEE. Seizure types of PEE were determined by both clinical observation by pediatric neurologists and ictal video-electroencephalography (EEG) recordings. RESULTS: Of the 44 patients after AESD, 10 (23%) had PEE. The period between the onset of encephalopathy and PEE ranged from 2 to 39 months (median 8.5 months). Cognitive impairment was more severe in patients with PEE than in those without. Biphasic seizures and status epilepticus during the acute phase of encephalopathy did not influence the risk of PEE. The most common seizure type of PEE on clinical observation was focal seizures (n = 5), followed by epileptic spasms (n = 4), myoclonic seizures (n = 3), and tonic seizures (n = 2). In six patients with PEE, seizures were induced by sudden unexpected sounds. Seizure types confirmed by ictal video-EEG recordings were epileptic spasms and focal seizures with frontal onset, and all focal seizures were startle seizures induced by sudden acoustic stimulation. Intractable daily seizures remain in six patients with PEE. SIGNIFICANCE: We demonstrate seizure characteristics of PEE in children after AESD. Epileptic spasms and startle focal seizures are common seizure types. The specific seizure types may be determined by the pattern of diffuse subcortical white matter injury in AESD and age-dependent reorganization of the brain network.

Microarray analysis of 50 patients reveals the critical chromosomal regions responsible for 1p36 deletion syndrome-related complications.

OBJECTIVE: Monosomy 1p36 syndrome is the most commonly observed subtelomeric deletion syndrome. Patients with this syndrome typically have common clinical features, such as intellectual disability, epilepsy, and characteristic craniofacial features. METHOD: In cooperation with academic societies, we analyzed the genomic copy number aberrations using chromosomal microarray testing. Finally, the genotype-phenotype correlation among them was examined. RESULTS: We obtained clinical information of 86 patients who had been diagnosed with chromosomal deletions in the 1p36 region. Among them, blood samples were obtained from 50 patients (15 males and 35 females). The precise deletion regions were successfully genotyped. There were variable deletion patterns: pure terminal deletions in 38 patients (76%), including three cases of mosaicism; unbalanced translocations in seven (14%); and interstitial deletions in five (10%). Craniofacial/skeletal features, neurodevelopmental impairments, and cardiac anomalies were commonly observed in patients, with correlation to deletion sizes. CONCLUSION: The genotype-phenotype correlation analysis narrowed the region responsible for distinctive craniofacial features and intellectual disability into 1.8-2.1 and 1.8-2.2 Mb region, respectively. Patients with deletions larger than 6.2 Mb showed no ambulation, indicating that severe neurodevelopmental prognosis may be modified by haploinsufficiencies of KCNAB2 and CHD5, located at 6.2 Mb away from the telomere. Although the genotype-phenotype correlation for the cardiac abnormalities is unclear, PRDM16, PRKCZ, and RERE may be related to this complication. Our study also revealed that female patients who acquired ambulatory ability were likely to be at risk for obesity.

The spectrum of ZEB2 mutations causing the Mowat-Wilson syndrome in Japanese populations.

Mowat-Wilson syndrome (MWS) is a multiple congenital anomaly syndrome characterized by moderate or severe intellectual disability, a characteristic facial appearance, microcephaly, epilepsy, agenesis or hypoplasia of the corpus callosum, congenital heart defects, Hirschsprung disease, and urogenital/renal anomalies. It is caused by de novo heterozygous loss of function mutations including nonsense mutations, frameshift mutations, and deletions in ZEB2 at 2q22. ZEB2 encodes the zinc finger E-box binding homeobox 2 protein consisting of 1,214 amino acids. Herein, we report 13 nonsense and 27 frameshift mutations from 40 newly identified MWS patients in Japan. Although the clinical findings of all the Japanese MWS patients with nonsense and frameshift mutations were quite similar to the previous review reports of MWS caused by nonsense mutations, frameshift mutations and deletions of ZEB2, the frequencies of microcephaly, Hirschsprung disease, and urogenital/renal anomalies were small. Patients harbored mutations spanning the region between the amino acids 55 and 1,204 in wild-type ZEB2. There was no obvious genotype-phenotype correlation among the patients. A transfection study demonstrated that the cellular level of the longest form of the mutant ZEB2 protein harboring the p.D1204Rfs*29 mutation was remarkably low. The results showed that the 3'-end frameshift mutation of ZEB2 causes MWS due to ZEB2 instability.

Clinical and biochemical characterization of 3-hydroxyisobutyryl-CoA hydrolase (HIBCH) deficiency that causes Leigh-like disease and ketoacidosis.

3-Hydroxyisobutyryl-CoA hydrolase (HIBCH) deficiency is an autosomal recessive disorder characterized by episodes of ketoacidosis and a Leigh-like basal ganglia disease, without high concentrations of pyruvate and lactate in the cerebrospinal fluid. Only 4 cases of HIBCH deficiency have been reported. However, clinical-biochemical correlation in HIBCH deficiency by determining the detailed residual enzyme activities has not yet been elucidated. Here, we report a case of two Japanese siblings with HIBCH deficiency carrying a new homozygous missense mutation (c.287C > A, [p.A96D]) at the substrate-binding site. A transfection study using HIBCH expression vectors harboring wild type or 4 reported mutations, including the newly identified mutation (p.A96D, p.Y122C, p.G317E, and p.K74Lfs*13), revealed a correlation between residual HIBCH activities and the severity of the disease. All HIBCH mutants, except p.K74Lfs*13, showed residual enzyme activity and only the patient with p.K74Lfs*13 had congenital anomalies. p.G317E showed only low enzyme activity (~ 3%) of that of wild-type HIBCH. Although p.A96D had approximately 7 times higher enzyme activity than p.G317E, patients with p.A96D died during childhood. These findings are essential for clinical management, genetic counseling, and specific meal and concomitant drug considerations as part of the treatment for patients with HIBCH deficiency.

Characteristics of epilepsy occurring in the first four months.

INTRODUCTION: Epilepsies with an onset during the early infantile period are relatively rare and their characteristics are not well recognized. The aim of this study was to determine the clinical characteristics of epilepsies with an onset during the early infantile period. METHODS: Clinical information on 73 patients with the onset of epilepsy within the first four months was collected from hospitals affiliated with Nagoya University. Patients were categorized into three groups: the idiopathic (20 patients), cryptogenic (19 patients), and symptomatic groups (34 patients). RESULTS: Fourteen (70%) of the 20 patients in the idiopathic group, nine (47%) of the 19 patients in the cryptogenic group, and 10 (29%) of the 34 patients in the symptomatic group had their first seizure within the first month of life. All patients in the idiopathic group, 12 patients (63%) in the cryptogenic group, and 18 patients (53%) in the symptomatic group had partial seizures (PS) alone throughout their clinical course. Four patients in the cryptogenic group and nine in the symptomatic group had PS at the onset, but evolved into spasms later. All patients in the idiopathic group, 13 patients (68%) in the cryptogenic group, and 13 patients (38%) in symptomatic group had experienced no seizures for at least one year at the time of the last follow-up. CONCLUSIONS: In patients with non-idiopathic epilepsy, an age-dependent evolution of seizure types was often observed. Recognition of this subgroup of patients could be important for the identification of appropriate candidates for early epilepsy surgery.

[Survival analysis for patients with severe motor and intellectual disabilities following tracheotomy].

To investigate the survival rate and causes of death in patients with severe motor and intellectual disabilities (SMIDs) that necessitated tracheotomy, we retrospectively analyzed 90 patients who underwent tracheotomy between 1990 and 2009. Indications for tracheotomy in these patients were upper airway obstruction (44 patients), recurrent aspiration pneumonia (28 patients), retained secretions (23 patients), prolonged mechanical ventilation (18 patients), chronic respiratory failure (9 patients), central respiratory failure (5 patients), and gastroesophageal reflux (8 patients). Most of the patients underwent tracheotomy at the age of 0-5 years or 10-19 years. As of April 1, 2010, 28 patients had died. The survival rate was 0.91 at 1 year, 0.74 at 5 years, 0.59 at 10 years, 0.54 at 15 years, and 0.40 at 19 years after tracheotomy. Massive tracheal bleeding due to development of tracheo-innominate artery fistulas occurred in 5 patients, and 4 of them died. They were thirteen years of age or older when they underwent tracheotomy, and developed fistulas after 2 weeks or later. In contrast, 7 patients at high risk for fistula formation, including those that had developed severe tracheomalacia associated with granulation or warning hemorrhages, underwent preventive resection of the innominate artery, and all of them had survived. It is important to regularly evaluate patients with SMIDs who have undergone tracheotomy by using bronchofiberscopy to identify risk factors for tracheoinnominate artery fistulas, a preventable cause of death.

A wide spectrum of clinical and brain MRI findings in patients with SLC19A3 mutations.

BACKGROUND: SLC19A3 (solute carrier family 19, member 3) is a thiamin transporter with 12 transmembrane domains. Homozygous or compound heterozygous mutations in SLC19A3 cause two distinct clinical phenotypes, biotin-responsive basal ganglia disease and Wernicke's-like encephalopathy. Biotin and/or thiamin are effective therapies for both diseases. METHODS: We conducted on the detailed clinical, brain MRI and molecular genetic analysis of four Japanese patients in a Japanese pedigree who presented with epileptic spasms in early infancy, severe psychomotor retardation, and characteristic brain MRI findings of progressive brain atrophy and bilateral thalami and basal ganglia lesions. RESULTS: Genome-wide linkage analysis revealed a disease locus at chromosome 2q35-37, which enabled identification of the causative mutation in the gene SLC19A3. A pathogenic homozygous mutation (c.958G > C, [p.E320Q]) in SLC19A3 was identified in all four patients and their parents were heterozygous for the mutation. Administration of a high dose of biotin for one year improved neither the neurological symptoms nor the brain MRI findings in one patient. CONCLUSION: Our cases broaden the phenotypic spectrum of disorders associated with SLC19A3 mutations and highlight the potential benefit of biotin and/or thiamin treatments and the need to assess the clinical efficacy of these treatments.

Frameshift mutations of the ARX gene in familial Ohtahara syndrome.

PURPOSE: Ohtahara syndrome is one of the most severe and earliest forms of epilepsy and is frequently associated with brain malformations, such as hemimegalencephaly. Recently, longer expansion of the first polyalanine tract of ARX was found to be causative for Ohtahara syndrome without brain malformation, whereas premature termination mutations of ARX were found to cause severe brain malformations, such as lissencephaly or hydranencephaly. Both are designated as ARX-related interneuronopathies. METHODS: We investigated the molecular basis of Ohtahara syndrome in two families, comprising six male patients in two generations demonstrating X-linked inheritance. RESULTS: Novel frameshift mutations in the terminal exon of the ARX gene (Ala524fsX534 and E536fsX672) were identified in two patients (2 and 13 years, each) from both families. Two patients developed West syndrome, and one of these later developed Lennox-Gastaut syndrome. Brain magnetic resonance imaging (MRI) of all patients showed no brain malformations in contrast to the patients with a premature termination mutation in other exons of ARX. DISCUSSION: The etiology of Ohtahara syndrome is heterogeneous; however, the molecular analysis of ARX should be considered in sporadic or familial male patients with Ohtahara syndrome.

[Various central nervous system involvements in dystrophinopathy: clinical and genetic considerations].

Duchenne and Becker muscular dystrophies, generically called dystrophinopathy, are caused by mutations of the dystrophin gene. It is not surprising that mutations of the dystrophin gene cause various neurological symptoms, since dystrophin protein is found in the brain tissue as well as in the muscle fiber cell membrane. However, few studies have reported on the frequency of central nervous complications other than mental retardation. Also, the relationship between the types of abnormal dystrophin gene and central nervous symptoms remains to be revealed. Medical records of 200 patients with dystrophinopathy from 167 extended families who had visited our institution during the past 15 years were reviewed to elucidate the frequency of central nervous complications. Fifty-four (27%) had mental retardation (an intelligence quotient less than 70), 15 (7.5%) had autism, 12 (6%) had epilepsy. 8 (4%) had febrile convulsion. 131 of these patients also underwent genetic testing. All patients with central nervous symptoms except one pair of siblings had some form of genetic deficiency or duplication distal to exon 44. Central nervous symptoms other than mental retardation are also common in patients with dystrophinopathy. These central nervous complications may be associated with mutations in the isoforms derived from exon 44 to 79.

Variations in aganglionic segment length of the enteric neural plexus in Mowat-Wilson syndrome.

BACKGROUND/PURPOSE: Patients with zinc finger homeo box 1B (ZFHX1B) mutations or deletions develop multiple congenital anomalies including Hirschsprung disease, known as Mowat-Wilson syndrome (MWS). In this study, we investigated variations in the enteric neural plexus abnormalities in MWS using morphometry-based histopathologic analysis. METHODS: Seven patients with MWS (3 with mutations in exon 8 of ZFHX1B and 4 with deletions) who had undergone modified Duhamel's operations for Hirschsprung disease were examined. Surgically resected rectosigmoid specimens were analyzed morphometrically. RESULTS: The length of the aganglionic segment was longer than 3 cm in all the patients with deletions. In 3 patients with mutations, the aganglionic region was not detected in the surgically resected specimens; however, the parameters of the ganglions and plexus were significantly smaller than those of controls (cloaca and aproctia), indicative of a transitional zone. Variation in the severity of pathological changes among the 3 patients with mutations was also noted. CONCLUSIONS: The variations in myenteric plexus pathologies in MWS appear to be caused by both variations in ZFHX1B abnormalities and epigenetic factors.

[Tracheostomy for home-care patients with severe motor and intellectual disabilities].

We discuss here the indication and complications of tracheostomy performed in 57 home-care pateints with severe motor and intellectual disabilities (SMID) during the past 13 years at our hospital. Thirty-five cases underwent tracheostomy following emergency endotracheal intubation for acute respiratory failure. Recently, the number of cases without preceding endotracheal intubation have increased. Many patients underwent tracheostomy at the age of 1 to 4 years and 10 to 14 years. The quality of life (QOL) of almost all the patients without preceding intubation markedly improved, as well as that of their families, and they were able to return to home. The most decisive reason for tracheostomy was secretions and recurrent aspiration pneumonia in 8 patients, gastroesophageal reflux in 4 and upper airway obstructions in 3. Several complications of tracheostomy were observed: tracheal granulations in 9 patients, tracheal malacia in 8, and tracheoinnominate artery fistula in 5. Among 8 patients with tracheal malacia, bleeding from the tracheoinnominate artery fistula occurred in 3. In 7 patients, self-made long tracheostomy tubes were necessary for the initial management of the tracheal malacia or tracheal granulations. Subsequently, made-to-order long tracheostomy tubes were used in three of these patients. In 12 patients, improved endotracheal T-tube with the tip sealed on the vocal cord side was used to prevent aspiration. Home-care SMID patients with respiratory disturbance require tracheostomy timely performed, followed by careful observation to prevent postoperative complications.

Evolution of seizures and electroencephalographical findings in 23 cases of deletion type Angelman syndrome.

Angelman syndrome (AS) is a genetic disorder with characteristic clinical and EEG findings. We report here the results of long-term follow-up studies on the epileptic seizures and EEG findings of 23 cases of deletion type AS confirmed by FISH analysis, including seven cases previously reported by Matsumoto et al. in 1992. The age at last follow-up in 23 patients was from 1 to 37 years of age (average: 18.0 years), with 10 patients (43.5%) in their 20s, and five over 30. Epileptic seizures were seen in all patients, and the age at seizure onset ranged from 3 to 50 months (average: 21.7 months). Status epilepticus was seen in 11 patients (47.8%). The percentages of cases seizure-free for more than 3 years were 25% (4/16) at 10 years of age, 70% (7/10) at 20, and 80% (4/5) at 30. The EEG findings were classified into six patterns according to the previous report: N (no spike, including focal slow waves), HVS (diffuse high-voltage slow bursts with or without spikes), F (focal spikes or multifocal spikes), S (diffuse spike and waves), C (continuous diffuse spike and waves), Hy (hypsarrythmia or hypsarrhythmia like waves). Hy was noted at ages 0-2 years in two cases. C was observed from the ages 2 to 15 years, being most frequently noted at 3-6 years of age, and it was never seen after 16 years of age. S was observed from ages 1 to 21 years. F was seen from 2 to 21 years of age, and most frequently during the ages of 2-7 years. HVS was seen from 0 years, and still remained after the age of 20. After 22 years of age, all patients showed N pattern including focal slow waves. One of the two patients who had bilateral frontal dominant delta slow waves in their 30s, had a recent seizure. Even if the spikes disappear with age, when bi-frontal focal slow waves remain, seizures may occur even in patients over 30.

[Clinical symptoms of the Rett syndrome patients with MECP2 gene abnormalities].

Mutations in a gene on the X-chromosome encoding methyl-CpG-binding protein 2 (MECP2) cause Rett syndrome. We examined clinical symptoms of 27 patients with Rett syndrome (aged 2 to 37 years), diagnosed by the criteria of the Rett Syndrome Diagnostic Criteria Work Group. having MECP2 gene mutations. Two novel MECP2 mutations, 119 del AG resulting in amino acid frame-shift 40fs43X and C to G transversion resulting in amino acid change of F157L, were found. All patients had the most important symptoms of this syndrome, including loss of acquired purposeful hand skills followed by stereotyped hand movements. Two patients had mild perinatal abnormalities. Nine showed psychomotor delay or hypotonia before 6 months. Five patients over 4 years old did not have microcephaly. Speech was preserved in five patients. According to the criteria, 18 cases were diagnosed as Rett syndrome variants. Sixteen out of 26 patients over 3 years old were able to walk (61.5%), and 22 had epilepsy (84.6%). Mutations of the 5 patients without microcephaly were R133C, P225R, R255X, R306C and 376fs386X, whereas those of the 5 variants with preserved speech were 34fs123X, R133C, R255X and R270. Common T158M mutation was detected in 4 patients, R255X in 7 and R270X in 4. Patients with the same mutations showed different phenotypes. Patients with R133C and R306C presented a mild phenotype without microcephaly. Of the proposed diagnostic criteria, the following three may not be essential: apparently normal prenatal and perinatal period, apparently normal psychomotor development through the first 6 months, and deceleration of head growth between 5 months and 4 years.