Harold Francis Falls: Eye geneticist and pioneer American medical geneticist

We report on a 20-year-old male with a β-glucuronidase (GUSB) deficiency mucopoly-saccharidosis. He had pectus carinatum, gross thoracic kyphoscoliosis, and hip dysplasia, a picture which became conspicuous after age 4 years. Hepatosplenomegaly, herniae, corneal clouding, and neurological abnormalities were absent. Although he had Alder-type granulations in his polymorpho-nuclear leukocytes, the urine did not contain a significant excess of mucopolysaccharides. Electron microscopic examination of skin and gingival biopsies, leukocytes, and cultured skin fibroblasts showed numerous single membrane-limited vacuoles either empty or filled with fibrillogranular material; this last tissue did not contain metachromatic granules. Radiographs demonstrated a distinct spondyloepiphyseal dysplasia in which the most striking changes were confined to the thoracic spine (flattening and collapse in T7, T8 and T10 vertebral bodies) and to the femoral capital epiphyses (irregularities and fragmentation). The activity of GUSB in the patient's serum, leukocytes, and fibroblasts was severely decreased; the GUSB activity in the serum and leukocytes from the parents and 2 asymptomatic sibs was subnormal. Immunoblot analysis showed very low levels of cross-reactive material towards anti-GUSB antiserum in the patient's leukocyte and fibroblast extracts. This patient was more severely affected in his skeleton than other described patients with an oligosymptomatic chronic form. This case broadens the clinical and biochemical picture associated with GUSB deficiency and may represent a new variant of the disease. © 1992 Wiley-Liss, Inc.     

Rapid screening for amyloid-related variant forms of transthyretin is possible by electrospray ionization mass spectrometry

We have used a new and rapid method to detect three variant forms of transthyretin (TTR): methionine for valine at position 30 (Met-30), serine for cysteine at position 6 (Ser-6) and methionine for leucine at position 111 (Met-111). By using an anti-transthyretin antibody and a centrifugal concentrator, transthyretin was isolated from plasma samples and analysed for variant forms by electrospray ionization mass spectrometry. Differentiation between homozygous and heterozygous transthyretin Met-30 and Met-111 posed no problems. However, a clear separation of transthyretin Ser-6 and Met-111 peaks in one patient with concordant Ser-6 and Met-111 mutations could not be achieved. The present method enables a quick and reliable detection of variant TTR. It can be used to screen families or small populations for abnormal TTR. Knowledge of TTR polymorphism and the variable expression of different amyloidogenic mutations should be taken into consideration when applying the methods in clinical practice.     

A review of venovenous haemofiltration in seriously ill infants

Abstract Between April 1989 and October 1991,13 severely ill infants, median age 13 days (range 1-180 days), median weight 3.5 kg (range 2.5-4.8 kg), received continuous venovenous haemofiltration (CVVH) for a median duration of 39 h (range 5-234 h). Filtration was performed through a double lumen catheter inserted into a central vein. The indications for filtration included acute renal failure (8), fluid overload (5), inborn errors of metabolism (3) and sepsis (1). Some infants had more than one indication. The median Paediatric Risk of Mortality (PRISM) score on the day of admission to the intensive care unit was 27 (range 8-42). No change in the level of respiratory support was required following the commencement of CVVH. Serum electrolyte concentrations and plasma osmolality remained normal throughout. Serum creatinine fell from a mean of 0.11 mmol/L (95% Cl 0.058-0.168) to 0.07 mmol/L (Cl 0.034-0.112). Urea fell from a mean of 9.5 mmol/L (Cl 4.4-14.6) to 6.5 mmol/L (Cl 2.7-10.3). Platelet counts fell by 40-50% from a mean of 126x10⁶/mm³ (Cl 72-180) to 69x 10⁶/mm³ (Cl 36-103) 18 h following commencement of filtration but no bleeding was encountered. The main complication was a thrombosis of the superior and inferior vena cava in one infant. Four infants survived to be discharged from intensive care. Continuous venovenous haemofiltration, with its inherent advantages over arteriovenous haemofiltration, is feasible in small infants using standard paediatric equipment.     

An insight into the biochemistry of inborn errors of metabolism for a clinical neurologist

Neurological dysfunction is an important manifestation of inherited metabolic disorders. Although these are more common in childhood, adult onset forms with a different clinical presentation are often encountered. Recent advances in the diagnosis and treatment of these conditions have substantially improved the outcome in many of these conditions. This makes it essential that the practicing physician be familiar with the clinical presentation and diagnosis of these disorders. For the evaluation of a patient with a possible inborn error of metabolism, simple screening tests may aid in the diagnosis and provide direction for more comprehensive laboratory analysis. In this review, we present a practical approach to diagnosis of neurometabolic disorders. Establishing a specific diagnosis in these disorders will enable the clinician in offering a definitive long-term treatment, prognosis and genetic counselling.     

Protein misfolding diseases: Prospects of pharmacological treatment

Protein misfolding has been linked to numerous inherited diseases. Loss‐ and gain‐of‐function mutations (common features of genetic diseases) may cause the destabilization of proteins, leading to alterations in their properties and/or cellular location, resulting in their incorrect functioning. Misfolded proteins can, however, be rescued via the use of proteostasis regulators and/or pharmacological chaperones, suggesting that treatments with small molecules might be developed for a range of genetic diseases. This work describes the potential of these small molecules in this respect, including for the treatment of congenital disorder of glycosylation (CDG) due to phosphomannomutase 2 deficiency (PMM2‐CDG).     

Hepatic endoplasmic reticulum storage diseases

ABSTRACT— Endoplasmic Reticulum Storage Diseases (ERSD) represent a novel group of inborn errors of metabolism affecting secretory proteins and resulting in hepatocytic storage and plasma deficiency of the corresponding protein. The hepatocellular storage is due to a molecular abnormality hindering the translocation of the abnormal protein from the rough (RER) to the smooth endoplasmic reticulum (SER). The molecular abnormality is genetically determined; hence it is hereditary, congenital, familial and permanent. The storage is selective and exclusive for the mutant protein and predisposes to the development of chronic cryptogenic liver disease. ERSD include alpha-1-antitrypsin deficiency, fibrinogen storage and alpha-1-antichymotrypsin deficiency. Basically, the diagnosis of ERSD is a morphological one: immunohistochemistry and electron microscopy are essential tools for their identification.     

3例Aicardi-Goutières综合征颅脑影像学表现及文献复习北大核心CSCD

目的结合文献回顾观察Aicardi-Goutières综合征(AGS)影像学表现。方法回顾性分析3例经基因检测证实的AGS患儿,患儿月龄分别为3、5、8个月,均接受颅脑MR检查,其中1例(病例3)接受颅脑CT检查,结合文献分析其颅脑MRI及CT表现。结果颅脑MRI显示,病例1双侧侧脑室、双侧额颞部脑外间隙增宽;病例2未见明显异常;病例3脑萎缩,双侧侧脑室前角旁异常呈T1WI等信号、T2WI及T2-液体衰减翻转恢复(T2-FLAIR)序列呈稍高信号。颅脑CT显示病例3脑萎缩,双侧基底核区、双侧侧脑室前角旁钙化,双侧侧脑室前角旁低密度灶。结论颅内钙化、脑萎缩和脑白质营养不良为AGS常见影像学表现。     

贵州省一家族性VonHippel-Lindau病的临床诊治和随访

目的分析贵州省一家族性VonHippel—Lindau病的临床特点、影像学表现、诊断治疗方法和预后。方法回顾性分析贵阳医学院附属医院1997年3月至2011年11月收治的1个家族性血管母细胞瘤家系（38人）7例患者的病史、临床表现、影像学相关资料。结果7例患者均未合并其他部位病变,MRI显示6例为实质性肿瘤,1例囊性肿瘤;4例患者共进行7次显微手术,切除血管母细胞瘤10枚,术后随访1例血管母细胞瘤在不同部位反复复发又经2次开颅手术、2次伽玛刀放射治疗;先证者在术后6年异位复发,复发病灶约为1mm,未予处理,继续随访;1例进行激光治疗视网膜血管瘤;2例症状不明显进行随访,在随访中未见新发病灶,原病灶也未增大。结论对于家族性血管母细胞瘤,头颅MRI检查是主要的诊断及随访方法,显微手术切除是主要治疗手段,立体定向放射治疗可作为补充治疗方法。由于家族性血管母细胞瘤易合并其他部位病变、复发率高、常为多发病灶,应加强对整个家族成员追踪随访和基因检测。     

Gingival biopsy in diagnosis of inborn storage diseases: a case of aspartylglycosaminuria

The case described is that of a 9-yr-old girl presenting with aspartylglycosaminuria. Diagnosis of this lysosomal storage disease was guided by histologic study of gingival specimen sampled in the course of dental care. Transmitted electron microscopy (TEM) revealed many vesicles and cellular inclusions, altered collagenic formations, associated with abnormal extracellular matrix. Gingival biopsy is easily performed, is noniatrogenic, leaves nor scar, and could be properly used to help diagnose metabolic diseases in children.     

Replacement therapy for inherited enzyme deficiency: Liver orthotopic transplantation in Niemann-Pick disease type A

Liver homotransplantation was attempted as replacement therapy in a 2-year-old patient with near total absence of sphingomyelinase activity typical of Niemann-Pick disease type A. Satisfactory function of the graft was observed until the death of the recipient from respiratory complication 2 years after transplantation. The clinical stigmata of the disease became less severe during the first 6 months after transplantation, with no further improvement thereafter. Sphingomyelinase activity was restored to near normal levels in serum, was present in cerebrospinal fluid and was maintained in the graft at normal or supranormal levels. No accumulation of sphingomyelin was observed in the transplanted organ as evaluated by histopathological and chromatographic studies. These findings support the interest of organ transplantation for long-term enzyme replacement in Niemann-Pick disease type A and similar lysosomal deficiencies.