Anti-epileptics alter hypothyroidism of patients with severe motor and intellectual disabilities.

Objective: Anti-epileptic drugs, such as carbamazepine (CBZ) or phenytoin, may induce hypothyroidism in epilepsy patients. We assessed thyroid function of chronic patients with severe motor and intellectual disabilities (SMID) in our hospital. Methods: We examined thyroid-stimulating hormone (TSH), free thyroxine (fT4), and free thyronine (fT3) in 73 patients with SMID (47 men and 26 women, average age 48.4 years, range 30-68 years) without thyroid hormone supplement therapy. We determined the relationship between the thyroid function of patients taking the anti-epileptic drugs CBZ, valproate (VPA), and phenobarbital, other medications including anti-psychotic drugs, and treatments without anti-epileptic or anti-psychotic drugs. Results: TSH levels were not significantly different between the groups taking CBZ (CBZ+med), other anti-epileptic drugs or anti-psychotic drugs (CBZ-med), and only medications without anti-epileptic or anti-psychotic drugs (Non-med). The CBZ+med group had significantly lower fT4 levels than the CBZ-med or Non-med groups. There was a negative correlation between thyroid function level and the phenobarbital groups. TSH levels of the VPA+med group were significantly higher than VPA-med and Non-med group; fT3 and fT4 levels were not significantly different. Conclusions: Our results indicate that hypothyroidism may be present in patients with SMID taking anti-epileptic drugs. This suggests it is important to regularly measure thyroid function in patients with SMID taking anti-epileptic drugs, especially CBZ.

A case of severe mental and developmental retardation associated with 14q terminal monosomy/5q terminal trisomy.

I previously described the case of a 19 year-old female with severe mental retardation, developmental retardation, microcephalus, short stature, bilateral microphthalmia, ptosis and blepharophimosis(1). Now, I present clinical descriptions of her half-siblings, who have a different father. Subtelomeric fluorescence in situ hybridization (FISH) analysis of the proband demonstrated 5q terminal trisomy and 14q terminal monosomy. I presume that her mother harbors a balanced translocation between the terminal of chromosome 5q and 14q. I suggest that familial cases of mental retardation and dysmorphic features should be screened for terminal chromosomal abnormalities by FISH or comparative genomic hybridization (CGH), even if G-banding analysis or high-resolution chromosome analysis is normal.

Congenital bilateral severe microphthalmia with mental retardation and cerebral palsy: chromosome aberration, 46, XY, t (2;6)(q31;q24).

Congenital bilateral anophthalmia and microphthalmia are rare conditions, with overall prevalence in one study set at 1.0 per 10,000 births. We report here a case of congenital bilateral severe microphthalmia with mental retardation and cerebral palsy. The patient was man aged 38 years with a chromosome aberration, namely a balanced translocation: 46, XY, t (2;6)(q31;q24). He had no other malformations apart from the severe microphthalmia. CT of the head showed no significant abnormal findings in the brain, but rudimentary eyeballs and external ocular muscles in the bilateral orbits. There was no family history of anophthalmia, microphthalmia, mental retardation or cerebral palsy. His mother had not used any medications or excessive alcohol during gestation. Putative genes of anophthalmia and microphthalmia reported to date include PAX6 (Glaser T et al 1994) and CHX10 (Ferda Percin E et al 2000). Further, some loci of these conditions have been reported (Graham CA et al 1991; Bessant DAR et al 1998; Morle L et al 2000: Forrester S et al 2001: Ng D et al 2002). To our knowledge, however, this is the first report of nonsyndromic microphthalmia or anophthalmia with chromosome 2q31 or 6q24 aberration. We consider that the putative gene may be located on the brake points of chromosome 2 and 6.

[Two cases of adult Down syndrome treated with selective serotonin re-uptake inhibitor for behavior disorders].

Adult patients with Down syndrome show psychological symptoms and early senility. Improving their environment and dealing with their complaints and stress should first address their behavioral problems, such as self-injury, depression, aggression and outbursts. Pharmacological treatment may also be tried for behavioral disorders. Individuals with Down syndrome demonstrate neurotransmitter changes such as the loss of acetylcholine, norepinephrine, and serotonin (5-HT) with increasing age. Selective serotonin re-uptake inhibitor (SSRI) is effective for depression and panic disorders. We report here the effect of SSRI in two adult male patients with Down syndrome, 35 and 47 years of age. Self-injury in one case and aggression and outbursts in another improved after 1 week of fluvoxamine treatment, suggesting the effects of SSRI for behavioral disorders of adult Down syndrome.

[A case of severe mental retardation with blepharophimosis, ptosis, microphthalmia, microcephalus, hypogonadism and short stature--the difference from Ohdo blepharophimosis syndrome].

We report a case of 13-year-old girl with short stature, microcephalus, blepharophimosis, ptosis, bilateral microphthalmia (more prominent in the right), hypogonadism, other minor anomalies, and severe mental retardation. Her mother had two spontaneous abortions. She was born as the second baby of dizygotic twins. The first baby died of diaphragm hernia and heart failure. Her body height, body weight and head circumference were below -3 SD. She did not have epicanthus inversus, hypoplastic teeth, heart anomalies, seizures, muscle weakness, and hearing loss. She was able to handle her wheelchair, but could neither understand nor speak meaningful words. When she looked at something in front of herself, she turned her face up and lifted the left eyelid with her own fingers. She had no somatic change of puberty. Laboratory and radiological examinations demonstrated a normal karyotype, normal bone age, findings of Chilaiditi syndrome, and absence of brain malformation on cranial CT. The serum levels of LH and FSH were high for age and those of estradiol and progesterone were low, suggesting immaturity of ovarian function. These findings suggested the ovarian functions might not get maturations. Hypogonadism has previously been reported in female cases of the blepharophimosis, ptosis and epicanthus inversus syndrome (BPES) type I, but not in those with the Ohdo blepharophimosis syndrome (OBS). Our case's condition differs from BPES because of the presence of mental retardation and the absence of epicanthus inversus. We also discuss the distinction from OBS, a disease entity of unknown etiology presenting with a variety of complications.

A case of adversive seizures induced by hyperventilation.

We report a case of adversive seizures featuring neck rotation and conjugate deviation induced by the hyperventilation maneuver. At the age of 6 years the patient suffered from conjugate deviation to the left. She herself felt no symptoms other than oculomotor symptoms. Hyperventilation induced an adversive seizure and ictal EEG showed sharp waves in the right frontal, central, and parietal areas. No brain image showed abnormal findings. Zonisamide completely attenuated her attacks. It is well known that hyperventilation induces absence seizures, and it has been reported that hyperventilation can induce complex partial seizures. However, no previous reports have described patients diagnosed as having adversive seizures with conjugate deviation induced by hyperventilation. We report the present case because, although its epileptogenesis is unknown, the patient is a rare case not only clinically but also electrophysiologically.

The longitudinal course of two cases with cretinism diagnosed after adolescence.

In Japan, mass screening tests on newborns for Cretinism have been performed since 1984, Cretinism is a very rare condition. We report the clinical course and complications of longitudinal thyroid hormone replacement therapy (liothyronine sodium: T3) of two women with Cretinism and ectopic thyroid gland for the past 33 years until 2001. They were born in April 1951 (Case 1) and in January 1952 (Case 2). On admission in June 1968, they were 17 and 16 years old. They had short stature, mental retardation, macroglossia, saddle nose, retardation of bone maturation, edematous face, coexistence of permanent teeth and deciduous teeth, abdominal distention, hypotonia, anemia, hypophosphatemia and hypercholesterolemia. After admission, Case 2 had an appendectomy for appendicitis. She was found to have a right ovarian cyst, but was not operated upon. Later, the right ovarian cyst disappeared during thyroid hormone replacement therapy. The complication in this case was NIDDM. Over secretion of thyroid hormone in for example, hyperthyroidism sometimes induces NIDDM. On their admission, a levothyroxine sodium (T4: Thyradin S) was unavailable in Japan, so we had no choice but to treat them with liothyronine sodium for thyroid hormone replacement therapy. We suspect that liothyronine sodium replacement therapy probably induced NIDDM. They experienced improved bone maturation, anemia, hypophsphatemia and hypercholesterolemia, but their intellectual and mental disabilities were not improved.

Eight novel mutations and functional impairments of the LDL receptor in familial hypercholesterolemia in the north of Japan.

In the course of investigations of familial coronary artery disease in Hokkaido, the northland of Japan, we identified 13 families affected by familial hypercholesterolemia. Among them, we identified eight novel mutations of the low-density lipoprotein (LDL) receptor gene, four of which caused frameshifts: (1) a 7-bp deletion at nucleotide (nt) 578-584 (codon 172-174, exon 4); (2) a 14-bp insertion at 682nt (codon 207-208, exon 4); (3) a 49-bp deletion at nt 943-991 (codon 294-310, exon 7); and (4) a one-base insertion of C to a stretch of C3 at nucleotides 1687-1689 or codon 542. The others included (5) a T-to-C transition at nt 1072 causing substitution of Cys for Arg at codon 337 (C337R, exon 8); (6) a splice-site G-to-T substitution in intron 11; (7) a splice-site G-to-C substitution in intron 11; and (8) a G-to-T transition at nt 1731 causing substitution of Trp for Cys at codon 556 (W556C, exon 12). To disclose the functional consequences of novel mutations, we characterized each of these mutations by two assays in peripheral lymphocytes, i.e., uptake of fluorescently labeled LDL by LDL receptors, and measurement of cell surface-bound LDL receptor protein using specific monoclonal antibody against LDL receptor.