Proof-of-principle for successful hematopoietic stem cell gene therapy has been provided for patients with Wiskott–Aldrich syndrome. In July 2013 the Italian San Raffaele Telethon Institute for Gene Therapy (HSR-TIGET) reported that three children with Wiskott–Aldrich syndrome showed significant improvement (improved platelet counts, immune functiona, and clinical symptoms) 20–30 months after being treated with a genetically modified lentivirus. In April 2015 results from a follow-up British and French trial six out of seven individuals showed improvement of immune function and clinical symptoms an average of 27 months after treatment with gene therapy. Importantly, neither study showed evidence of leukemic proliferation following treatment, a complication of early attempts at gene therapy using a retroviral vector. It is unknown why these gene therapies did not restore normal platelet numbers, but gene therapy treatment was still associated with transfusion-independence and a significant reduction in bleeding events. A version of this treatment, OTL-103, is being developed by Orchard Therapeutics and (as of 28 June 2021) is undergoing Phase I/II clinical trials. Prognosis
Outcomes from Wiskott–Aldrich syndrome are variable and depend on how severely an individual is affected (the WAS score may be used to assess disease severity). The milder end of the disease spectrum associated with the WAS gene is referred to as X-linked neutropenia or X-linked thrombocytopenia, and the latter is thought to have a normal life expectancy with reports of minimally affected males surviving into their seventh decade without treatment. Traditionally however Wiskott–Aldrich syndrome has been associated with premature death from causes including bleeding, infections, or malignancy.
There have also been reports of diabetes insipidus complicating this condition.Many laboratory abnormalities are seen in acute fatty liver of pregnancy. Liver enzymes are elevated, with the AST and ALT enzymes ranging from minimal elevation to 1000 IU/L, but usually staying in the 300-500 range. Bilirubin is almost universally elevated. Alkaline phosphatase is often elevated in pregnancy due to production from the placenta, but may be additionally elevated. Other abnormalities may include an elevated white blood cell count, hypoglycemia, elevated coagulation parameters, including the international normalized ratio, and decreased fibrinogen. Frank disseminated intravascular coagulation, or DIC, may occur in as many as 70% of people.Abdominal ultrasound may show fat deposition in the liver, but, as the hallmark of this condition is microvesicular steatosis (see pathology below), this is not seen on ultrasound. Rarely, the condition can be complicated by rupture or necrosis of the liver, which may be identified by ultrasound. Pathophysiology
The understanding of the causes of acute fatty liver of pregnancy
has been improved by advances in mitochondrial biochemistry. Deficiency of LCHAD (3-hydroxyacyl-CoA dehydrogenase) leads to an accumulation of medium and long chain fatty acids. When this occurs in the foetus, the unmetabolized fatty acids will re-enter the maternal circulation through the placenta, and overwhelm the beta-oxidation enzymes of the mother. The gene responsible for LCHAD has been isolated, and the most common mutation found in acute fatty liver of pregnancy is the E474Q missense mutation. LCHAD deficiency is autosomal recessive in inheritance and mothers are often found to be heterozygous for the affected mutation.