The muscle weakness often causes delay of motor skills such as crawling and walking. Additionally, affected individuals tend to experience extreme tiredness fatigue during strenuous physical activity. Most males with Barth syndrome have neutropenia.
The levels of white blood cells can be consistently low persistent , can vary from normal to low intermittent , or can cycle between regular episodes of normal and low cyclical. Neutropenia makes it more difficult for the body to fight off foreign invaders such as bacteria and viruses, so affected individuals have an increased risk of recurrent infections.
Newborns with Barth syndrome are often smaller than normal, and their growth continues to be slow throughout life. Some boys with this condition experience a growth spurt in puberty and are of average height as adults, but many men with Barth syndrome continue to have short stature in adulthood.
Males with Barth syndrome often have distinctive facial features including prominent cheeks. Affected individuals typically have normal intelligence but often have difficulty performing tasks involving math or visual-spatial skills such as puzzles. Males with Barth syndrome have increased levels of a substance called 3-methylglutaconic acid in their blood and urine. The amount of the acid does not appear to influence the signs and symptoms of the condition.
Barth syndrome is one of a group of metabolic disorders that can be diagnosed by the presence of increased levels of 3-methylglutaconic acid in urine 3-methylglutaconic aciduria. Even though most features of Barth syndrome are present at birth or in infancy, affected individuals may not experience health problems until later in life.
The age at which individuals with Barth syndrome display symptoms or are diagnosed varies greatly. The severity of signs and symptoms among affected individuals is also highly variable. Males with Barth syndrome have a reduced life expectancy. Many affected children die of heart failure or infection in infancy or early childhood, but those who live into adulthood can survive into their late forties.
Barth syndrome is estimated to affect 1 in , to , individuals worldwide. More than cases have been described in the scientific literature. This protein is located in structures called mitochondria, which are the energy-producing centers of cells.
The tafazzin protein is involved in altering a fat lipid called cardiolipin, which plays critical roles in the mitochondrial inner membrane. Once altered by tafazzin, cardiolipin is key in maintaining mitochondrial shape, energy production, and protein transport within cells.
As a result, tafazzin cannot alter cardiolipin, and levels of functional cardiolipin are reduced. In addition, for unknown reasons, a variant of cardiolipin called monolysocardiolipin MLCL is formed. The disease affects many body systems from fetal through to adult life, making this an important condition for obstetricians, geneticists, general paediatricians, cardiologists and neurologists to be aware of, especially since rapid definitive biochemical testing has recently become available[ 7 ].
Inclusion criteria for the Registry are a diagnosis of BTHS, mutation of the causative gene and the provision of informed consent. There is no known racial or ethnic predilection. Evidence is, however, growing that the disease may be under-diagnosed.
Further information about frequency is described in the section on cardiological aspects of the disease. The TAZ sequence is highly conserved in evolutionary terms[ 13 ]. Most are missense mutations and small insertions or deletions, but a minority of patients have large exon, or in one case whole gene, deletion[ 15 ]. Frameshift mutations causing tafazzin truncation and mutations affecting splice donor or acceptor sites have also been identified.
Mutations have been reported in all exons of TAZ, including a variant of unknown significance in exon 5[ 16 ]. Gonadal mosaicism has also been documented[ 18 ], raising the small possibility that a woman who does not herself carry mutations in her somatic DNA may have more than one affected boy. Although it is theoretically possible for a female to manifest symptoms of BTHS due to skewed X-inactivation, the only female ever described with the disease had abnormalities of both X chromosomes[ 19 ].
One was a ring form with a large deletion of the long arm including the Xq28 region and the second had a large deletion of exons 1—5 of TAZ.
Problems in this patient included intrauterine growth retardation and the development of severe dilated cardiomyopathy DCM with left ventricular non-compaction LVNC at one month of age. Both highly skewed and non-skewed patterns of X-inactivation were present among females within the same family.
It has been postulated that a post-inactivation selection mechanism might operate due to the TAZ protein causing respiratory chain abnormalities or other deleterious effects in multiple cell types[ 20 ]. TAZ encodes an acyltransferase that catalyses the remodeling of cardiolipin in mitochondrial membranes[ 6 , 21 — 23 ].
TAZ mutations reduce formation of L4-CL in favor of cardiolipin molecules of different acyl composition and cause an accumulation of intermediate species carrying three rather than four linoleoyl acyl groups monolysocardiolipins [MLCL] [ 25 , 26 ]. This leads to a markedly increased MLCL:L4-CL ratio[ 27 ] and now forms the basis for a sensitive and apparently specific test for the disease[ 7 , 28 ].
Cardiolipin has an important role in maintaining mitochondrial structure[ 29 ], associates with a number of mitochondrial proteins reviewed in[ 30 ] and is also involved in mitochondrial apoptosis reviewed in[ 31 ]. In particular, cardiolipin stabilises highly ordered respiratory chain supercomplexes and optimises energy production in mitochondria[ 32 , 33 ].
Evidence for a role of cardiolipin in maintaining mitochondrial integrity is supported by varying degrees of structural and functional abnormalities of mitochondria isolated from BTHS patients[ 1 , 23 , 34 , 35 ].
The myocyte cytoplasm contains increased numbers of mitochondria, most being larger than normal. Lipid is not increased but pools of non-membrane bound glycogen are evident. B Higher power electron micrograph. The mitochondria are enlarged and are crowded together, with many touching one another.
The cristae are not parallel but are stacked, and many are in abnormal circular arrays red arrow. The nucleus starred is centrally placed, but the myofilaments, with their cross-striations blue arrows , are displaced to the periphery of the cell. C High power photomicrograph of myocardium stained with Masson-Trichrome stain. The myocytes are vacuolated with pale areas around the nucleus. In some giant mitochondria are visible as rounded, red bodies [arrows].
Such giant mitochondria are very suggestive of mitochondrial pathology and reflect the giant mitochondria seen on electron microscopy. Because research into the pathogenesis of BTHS in humans has until recently been hampered by the inability to make a mammalian model, most in vivo and in vitro studies have used yeast, fruit flies, zebrafish and cultured cells, as well as patient metabolic studies[ 36 — 42 ]. No significant cardiac effects were apparent in two-month-old mice, but by eight months of postnatal TAZ knockdown, a range of structural abnormalities of cardiac sarcomeres and mitochondria, and of cardiac structure and function, were apparent.
The latter included left ventricular dilatation and dysfunction. The effect on skeletal muscle was more marked, with obvious ultrastructural changes apparent by two months. This model holds promise for furthering our understanding of the pathogenesis of BTHS and for testing candidate gene or drug therapies. The most widely recognised features of the disease comprise CM, skeletal myopathy, neutropenia, growth delay and increased urinary excretion of 3-MGCA[ 3 ].
However, a much broader phenotype is now recognised Table 1. The majority of the information about BTHS comes from individual case reports and small cases series, although detailed analyses of 34 and 73 patients respectively were published in [ 44 ] and [ 4 ].
Endocardial fibroelastosis in BTHS. A The endocardium appears abnormally pale starred and B there is marked thickening arrowed of the endocardial surface on the corresponding photomicrograph Van Gieson staining.
A comprehensive Australian study[ 49 ] suggested that 4. This substantial proportion suggests that all young males with unexplained DCM should be investigated for BTHS, especially those presenting as neonates or within the first year. The potential for fetal onset of CM in BTHS, which has been documented as early as 18 weeks gestation[ 50 ], has important implications which are discussed in the section on miscarriage and stillbirth.
For example, one patient presented acutely with severe DCM during primary infectious mononucleosis personal communication, Dr Wilf Kelsall and others coincident with a variety of proven respiratory viral infections. BTHS should therefore be included in the differential diagnosis of males presenting with DCM of apparent viral aetiology, especially where neutropenia is present which could mistakenly be ascribed to secondary bone marrow suppression by viral infection.
This tendency to spontaneous marked improvement of BTHS features may support clinicians in their belief that a patient in whom the diagnosis of BTHS has been missed is recovering from a strictly viral cardiomyopathy. Spencer et al. There is a variable but usually overall good response to medical therapy for cardiac failure in BTHS.
Thus, 16 of 30 fully evaluable BTHS patients in this study had normal left ventricular ejection fractions, although 10 of these were taking at least one cardiac medication. Some patients respond well to therapy initially but deteriorate after months or years of stability, necessitating cardiac transplantation[ 4 ].
Age at time of cardiac transplant is shown in Figure 3. Age at cardiac transplantation in BTHS patients. Age is shown at the time of first transplant where multiple transplant procedures were required data supplied by BSF.
It should be noted that there were sometimes extended periods between initial listing for cardiac transplantation and performance of procedures data unavailable.
There is also a risk of ventricular arrhythmia and sudden cardiac death in BTHS, which appears to be independent of the degree of CM[ 11 , 51 , 52 ]. These arrhythmias can occur at times of apparent good health. When studying a larger cohort, Spencer et al. Most of the documented serious arrhythmias have been in older children but life threatening arrhythmias have been observed in younger children, including two deaths related to ventricular arrhythmia in babies unpublished observations.
BTHS can also present as sudden cardiac death within families, as illustrated by a previous family history of sudden cardiac death in two BTHS patients with documented arrhythmias[ 53 ]. Prolonged or borderline prolonged long QTc has been found in children with HCM and DCM due to other causes and may reflect the underlying cardiac muscle abnormality, which in BTHS includes myofibrillar disorganization[ 54 ]. Others have postulated that cardiolipin abnormalities could impede cross-communication between the endoplasmic reticulum and mitochondria, thus affecting calcium handling in cardiomyocytes and cardiac conducting cells[ 43 ].
Neutropenia sometimes precedes other features, and has even been documented in a cord blood sample[ 1 ]. Nadirs in the neutrophil count are associated with bacterial infection ranging from prolonged upper respiratory tract infections, mouth ulcers, inflamed gums and perianal dermatitis to overwhelming sepsis and multi-organ failure.
Recognition of neutropenia and, therefore, correct diagnosis of BTHS can be delayed because neutrophil counts often increase to normal or supranormal within a few days of developing an infection[ 3 ]. Unpredictable neutropenia in a BTHS patient. This graph shows a routine neutrophil profile from a BTHS patient who was not receiving G-CSF and had no clinical explanation for changes in neutrophil counts. It demonstrates that some BTHS patients can transition rapidly from severe neutropenia to high normal neutrophil counts.
Furthermore, BTHS patients can present with bacterial infection in the context of a normal neutrophil count, infection having commenced when severely neutropenic just one or two days previously. Concurrence of severe neutropenia, CM, mitochondrial dysfunction, low muscle mass and a propensity to hypoglycaemia and lactic acidosis may all increase the likelihood of death in response to severe bacterial infection, making BTHS an underlying diagnosis to consider in patients dying with bacterial sepsis.
Neutropenia in BTHS is associated with myelocyte arrest on bone marrow aspiration[ 1 ] see Figure 5 and compensatory monocytosis peripherally[ 3 ]. Although absolute neutrophil counts ANCs for some boys fluctuate within a relatively narrow range, others have wide and unpredictable swings in their ANCs.
A bone marrow aspirate from a patient with BTHS showing typical myelocyte arrest. There is an excess of monocytes and absence of mature neutrophils. The mechanism of neutropenia and infection in BTHS is under continuing debate. Barth et al showed in their original studies that neutrophil function was normal[ 1 ]. It has since been postulated that there may be increased neutrophil apoptosis or increased clearance of neutrophils by tissue macrophages, although this has not been supported in studies[ 55 , 56 ].
This has led to the hypothesis that the defect in BTHS might operate at the level of neutrophil precursors in bone marrow; Aprikyan et al transfected TAZ -specific shRNA constructs into human myeloid progenitor HL60 cells and showed that knockdown of TAZ gene expression by several constructs was associated with elevated dissipation of mitochondrial membrane potential, compared to that of control cells transfected with scrambled shRNA[ 57 ].
Skeletal myopathy is widely recognised in BTHS, and most boys have at least mildly delayed gross motor milestones[ 44 , 58 ]. Grip strength can be reduced, tending to improve through the first decade and stabilise during adolescence, although distal muscle weakness is not a prominent component of the disease[ 44 ]. Patients with BTHS are able to walk but often find normal activities, such as kicking a ball or running, difficult. The evolution of disabling myopathy has been described at between 43 and 50 years in one man subsequently diagnosed with BTHS; his electromyogram was consistent with severe, chronic myopathy and creatine phosphokinase was slightly elevated[ 17 ].
Boys tend not to have classic myopathic facies, or involvement of extra-ocular or diaphragmatic muscles. Poor tone can result in lumbar lordosis. Easy fatigability is a major problem in BTHS and some boys use mobility aids to conserve energy. Screening patients with unexplained mitochondrial myopathy has already identified one BTHS patient[ 28 ].
It is, however, important to note that muscle biopsy has no role in the elective diagnosis of a patient with suspected BTHS. A small study demonstrated significantly weaker visuospatial and visual motor scores on neuropsychological testing, and a non-significant tendency towards lower scores in mathematics, than in a control population[ 63 ].
Detailed neuropsychological assessment of a larger patient group is currently being performed personal communication, Dr. Vanessa Garratt. Stroke is also a significant risk in BTHS patients, mostly in the context of severe cardiac failure and possibly related to clot formation in the increased ventricular trabeculations often seen in BTHS. Middle cerebral artery occlusion has been reported in one year-old patient with severe DCM[ 64 ] but 12 other patients are known to the BSF, including one who developed fatal clots shortly after going onto a Berlin Ventricular Assist Device unpublished observations, Valerie Bowen.
However, cases have been reported where urinary 3-MGCA levels have been normal in patients with TAZ mutations[ 45 , 50 , 61 , 65 — 67 ] and levels may vary considerably even within a 24 hour period[ 9 ]. Although many boys with BTHS never experience significant metabolic problems, a range of metabolic abnormalities have been reported which may alert clinicians to consideration of the diagnosis. Lactic acidosis and hypoglycaemia appear to be more common in the neonatal period and infancy.
Several cases of acute metabolic decompensation and death have been described in neonates[ 52 , 69 ]. Ongoing studies on the intermediary metabolism of BTHS suggest that secondary abnormalities of citric acid cycle function sufficiently affect anaplerosis and amino acid metabolism to cause inadequate muscle protein synthesis unpublished observations, Dr Richard Kelley.
Various attempts at targeting the metabolic derangements in BTHS have been tried, including the use of L-carnitine[ 70 ] or pantothenic acid[ 71 ]. Most patients treated with pantothenic acid supplements have failed to show benefit representative examples reported in[ 72 ].
More recently, the identification of consistently low levels of specific amino acids have led to dietary supplementation with arginine and other amino acids but there is as yet no published data on these observations or treatment.
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