ABSTRACT
BACKGROUND: Infantile neuroaxonal dystrophy (INAD) is a rare, autosomal recessive disease due to defects in PLA2G6 and is associated with lipid peroxidation. RT001 is a di-deuterated form of linoleic acid that protects lipids from oxidative damage. METHODS: We evaluated the pharmacokinetics (PK), safety, and effectiveness of RT001 in two subjects with INAD (subject 1: 34 months; subject 2: 10 months). After screening and baseline evaluations, subjects received 1.8 g of RT001 BD. PK analysis and clinical evaluations were made periodically. MAIN FINDINGS: Plasma levels of deuterated linoleic acid (D2-LA), deuterated arachidonic acid (D2-AA), D2-LA to total LA, and D2-AA to total AA ratios were measured. The targeted plasma D2-LA ratio (>20%) was achieved by month 1 and maintained throughout the study. RBC AA-ratios were 0.11 and 0.18 at 6 months for subjects 1 and 2; respectively. No treatment-related adverse events occurred. Limited slowing of disease progression and some return of lost developmental milestones were seen. CONCLUSIONS: Oral RT001 was administered safely in two subjects with INAD. Early findings suggest that the compound was well tolerated, metabolized and incorporated in the RBC membrane. A clinical trial is underway to assess efficacy.
ABSTRACT
Mucopolysaccharidosis Type IVA (MPS IVA), also known as Morquio A syndrome, is an autosomal recessive lysosomal storage disorder that results from variants in the GALNS gene that encodes the enzyme galactosamine-6-sulfate sulfatase. This syndrome has systemic manifestations including, but not limited to, musculoskeletal, respiratory, cardiovascular, rheumatologic, neurologic, dental, ophthalmologic, and otologic. This condition is usually detected within the first few years of life with an average life expectancy of 25.3 ± 17.43 years. We report the natural history of two of the oldest known females with MPS IVA, who were each clinically diagnosed at 4 years of age and who are now 74 and 70 years of age, respectively. They are both affected by pathogenic variants c.319G>A (p.Ala107Thr) and c.824 T>C (p.Leu275Pro) in the GALNS gene.
Subject(s)
Chondroitinsulfatases/genetics , Mucopolysaccharidosis IV/genetics , Aged , Female , Humans , Mucopolysaccharidosis IV/epidemiology , Mucopolysaccharidosis IV/pathology , Mutation/geneticsABSTRACT
Microcephalic primordial dwarfism (MPD) is a class of disorders characterized by intrauterine growth restriction (IUGR), impaired postnatal growth and microcephaly. Majewski osteodysplastic primordial dwarfism type II (MOPD II) is one of the more common conditions within this group. MOPD II is caused by truncating mutations in pericentrin (PCNT) and is inherited in an autosomal recessive manner. Detailed growth curves for length, weight, and OFC are presented here and derived from retrospective data from 26 individuals with MOPD II confirmed by molecular or functional studies. Severe pre- and postnatal growth failure is evident in MOPD II patients. The length, weight, and OFC at term (when corrected for gestational age) were -7.0, -3.9, and -4.6 standard deviation (SD) below the population mean and equivalent to the 50th centile of a 28-29-, 31-32-, and 30-31-week neonate, respectively. While at skeletal maturity, the height, weight, and OFC were -10.3, -14.3, and -8.5 SD below the population mean and equivalent to the size of 3-year 10- to 11-month-old, a 5-year 2- to 3-month-old, and 5- to 6-month-old, respectively. During childhood, MOPD II patients grow with slowed, but fairly constant growth velocities and show no evidence of any pubertal growth spurt. Treatment with human growth hormone (n = 11) did not lead to any significant improvement in final stature. The growth charts presented here will be of assistance with diagnosis and management of MOPD II, and should have particular utility in nutritional management of MOPD II during infancy.
Subject(s)
Antigens , Dwarfism/diagnosis , Dwarfism/genetics , Fetal Growth Retardation/diagnosis , Fetal Growth Retardation/genetics , Growth Charts , Microcephaly/diagnosis , Microcephaly/genetics , Mutation , Osteochondrodysplasias/diagnosis , Osteochondrodysplasias/genetics , Adolescent , Adult , Body Height , Body Weight , Child , Child, Preschool , Dwarfism/drug therapy , Female , Fetal Growth Retardation/drug therapy , Human Growth Hormone/therapeutic use , Humans , Male , Microcephaly/drug therapy , Osteochondrodysplasias/drug therapy , Young AdultABSTRACT
A description of the clinical features of Majewski osteodysplastic primordial dwarfism type II (MOPD II) is presented based on 58 affected individuals (27 from the literature and 31 previously unreported cases). The remarkable features of MOPD II are: severe intrauterine growth retardation (IUGR), severe postnatal growth retardation; relatively proportionate head size at birth which progresses to true and disproportionate microcephaly; progressive disproportion of the short stature secondary to shortening of the distal and middle segments of the limbs; a progressive bony dysplasia with metaphyseal changes in the limbs; epiphyseal delay; progressive loose-jointedness with occasional dislocation or subluxation of the knees, radial heads, and hips; unusual facial features including a prominent nose, eyes which appear prominent in infancy and early childhood, ears which are proportionate, mildly dysplastic and usually missing the lobule; a high squeaky voice; abnormally, small, and often dysplastic or missing dentition; a pleasant, outgoing, sociable personality; and autosomal recessive inheritance. Far-sightedness, scoliosis, unusual pigmentation, and truncal obesity often develop with time. Some individuals seem to have increased susceptibility to infections. A number of affected individuals have developed dilation of the CNS arteries variously described as aneurysms and Moya Moya disease. These vascular changes can be life threatening, even in early years because of rupture, CNS hemorrhage, and strokes. There is variability between affected individuals even within the same family.
