Secondary Logo

Journal Logo

Gross Motor Development of a Toddler with Barth Syndrome, an X-Linked Recessive Disorder: A Case Report

Jarvis, Moon SPT; Garrett, Penny MS, PT; Svien, Lana MA, PT

Special Report on Genetics

Purpose The purpose of this case report is to describe the gross motor development of a toddler with Barth Syndrome, an X-linked genetic disorder.

Summary of Key Points Barth Syndrome is an unusual pediatric cardiovascular and neuromuscular disorder with a combination of features, including dilated cardiomyopathy, persistent aciduria, skeletal myopathy, severe neutropenia, and growth retardation. The child described in this report has a complicated medical history, including the diagnosis of Barth syndrome at 38 months of age. He began receiving early intervention services, including physical therapy, because of developmental delays at 13 months. This report was written when the child was 45 months old. Implications for working with a child with a cardiomyopathy and neutropenia are presented. Cardiovascular changes following transcatheterization for an atrial septal defect are described. Developmental changes secondary to an early intervention program that included physical therapy are discussed.

Recommendations Multiple aspects of care need to be considered when working with a child with a genetic syndrome that involves a cardiac defect and cardiomyopathy. When working with a child with a known cardiomyopathy, the physical therapist must watch for signs of cardiores-piratory distress. In addition, neutropenia is often associated with Barth syndrome, so the therapist must be cognizant of exposing the child to any illnesses.

Physical Therapy Department (M.J., L.S.), University of South Dakota School of Medicine, Vermillion, SD, and Western Hills Area Education Agency (P.G.), LeMars, Iowa

Address correspondence to: Lana Svien, MA, PT, Physical Therapy Department, School of Medicine, University of South Dakota, 414 E. Clark Street, Vermillion, SD 57069. Email:

Back to Top | Article Outline


In 1983, Barth et al. described a pedigree with an unusual pediatric neuromuscular disease showing a combination of features, including dilated cardiomyopathy, 1,3 persistently elevated levels of 3-methylgluconic acid in the urine 1–3 (<10 μmol/mmol creatine), 4 skeletal myopathy, 1–3 severe neutropenia 1–3 (<1.5 × 109 L), 4 and growth retardation. 1–3

Barth syndrome is a severe disorder that is often fatal in childhood 5 as a result of heart failure 4 or infections. 3 However, survival to later childhood has been reported. 4 This rare metabolic disorder has been reported to occur on three continents: Europe, North America, and Australia. 6 The incidence of Barth syndrome is thought to be between 1 in 50,000 and 1 in 150,000, but this may be an underestimate. 3

Barth syndrome is an X-linked recessive disorder 3,5 with mutations recently identified in the G4.5 gene (Xq28), an encoding group of 10 proteins collectively labeled tafazzin. 4 The effect of the tafazzin protein group depends on the manner in which they splice and transcribe, giving them a number of actions. 4 Female carriers of this syndrome do not show clinical symptoms. 3 Common impairments for male infants in the newborn period or within the first few months of life are hypotonia and clinical signs of a cardiomyopathy, such as diminished tolerance to self-induced movement and exertional dyspnea. 3,7 Birth weight is slightly reduced or within normal limits, but there seems to be a marked deceleration of growth, and by age two years, weight and height average four standard deviations below normal. 3 Normal or low-normal adult height may be achieved after the pubertal years, but before that height and weight remain below but parallel to the third percentile. 3

A prospective study of children with Barth syndrome found other impairments, including failure to thrive, variable neutropenia, mild generalized weakness, a partial Gower’s sign 3,4 (walking up one’s legs with one’s hands to attain erect standing 8), delayed gross motor milestones, and a waddling gait. 3 Learning disabilities, especially in areas of visual-spatial perception and arithmetic reasoning, have also been reported. 3 Common school problems include easy fatigability with sustained fine motor activites. 3

Many children with Barth syndrome require cardiac medications such as diuretics and digitalization. All fevers and localized infections are given immediate attention. 3 No articles published on Barth syndrome include a description of the gross motor development of a child with this syndrome or a discussion of the importance, benefit, or need for physical rehabilitation services, even though authors of other articles in the literature have substantiated the benefit of intervention for children with congenital heart defects. 9,10

It has been reported that parents who have a child with congenital heart defects may perceive their infant as more difficult than a healthy baby, which can have ramifications for parental attachment. 9 A study by Marino and Lipshitz 9 found that infants with cardiac disease were more withdrawn and had lower thresholds for stimulation than healthy children. The toddlers were less active, less rhythmic, and more negative in mood than healthy children. The authors also point out that children with congenital heart defects display temperament instability during the first three years of life. 9 The infants tend to want to conserve energy, which in turn reduces their overall fitness and endurance. This lack of physical activity can also impede cardiovascular, musculoskeletal, and psychosocial development. 10

The purpose of this retrospective case report is to report the outcomes of Cody, a three-year-old boy with Barth syndrome. The examination, intervention, and outcomes before and after implantation of a device to repair an atrial septal defect are described. Parental consent was given for Cody to participate in this case study.

Back to Top | Article Outline


Birth History

Cody was born at 37 weeks’ gestation, and, with a birth weight of 5 lb, 10.5 oz, his size was average for gestational age. His mother was a 29-year-old gravida 2, para 1 (two pregnancies, one viable birth). The first pregnancy resulted in an infant who did not survive. Six months before Cody’s birth, a chorionic villous sample was obtained, revealing a normal 46,XY male karyotype. Evaluation of the placenta showed a two-vessel umbilical cord. Normally the umbilical cord contains two umbilical arteries and one umbilical vein. 11 At birth, Cody’s Apgar score was 8. He was initially admitted to the nursery for healthy infants.

Back to Top | Article Outline

Complications During Infancy

At birth Cody exhibited multiple minor dysmorphic features, including a large, flat fontanelle; somewhat wide-spaced eyes; slightly low-set ears; and a thin philtrum. He had slight, bilateral fifth-finger clinodactyly (abnormal bending of the fingers). 12 He also had short, puffy-looking feet and a persistent problem with scrotal edema through the first couple of weeks.

At his first feeding, Cody was tachypneic and had some emesis. Because of continued respiratory distress, he was transferred to the intensive care nursery. A chest x-ray revealed findings consistent with neonatal pneumonia. An echocardiogram revealed a patent ductus arteriosus with a left-to-right shunt, some aneurysmal formation of the atrial septum, and what appeared to be a possible patent foramen ovale. The ductus arteriosus and foramen ovale usually close soon after birth. 11

A chest x-ray performed 19 days after birth showed a persistent density in the right cardiophrenic angle. By that time his lung fields were significantly cleared.

Twenty-one days after birth, Cody was transferred to a children’s hospital because of failure to thrive and apparent cardiomyopathy. At 21 days old, he weighed 2.72 kg (fifth percentile) and was 49 cm tall (10th percentile). His vital signs were as follows: heart rate, 164 beats/min; respirations, 70/min; and blood pressure, 54/28 mm Hg. Normal vital signs (birth to one month) are heart rate, 120 to 200 beats/min; respirations, 35 to 55/min; and blood pressure, 60 to 90/30 to 60 mm Hg. 8 Once Cody was transferred to the children’s hospital, cardiac catheterization and myocardial biopsy were performed. The biopsy samples showed fibrosis of the cardiac muscle. Genetic testing revealed normal chromosomes. Organic acids were tested when Cody was one month old. At that time there were no abnormal findings. He was discharged from the children’s hospital at age 35 days with the following diagnoses: 1) failure to thrive due to cardiomyopathy; 2) cardiomyopathy of unknown etiology; 3) bilateral inguinal hernias, resolved; and 4) a single right kidney.

One month after discharge from the children’s hospital, he had a follow-up visit with the pediatric cardiologist. He was eight weeks old and weighed 3.7 kg, and his vital signs were within normal limits for his age: heart rate, 150 beats/min; respirations, normal; and blood pressure, 106/72 mm Hg. A systolic murmur was noted at this exam. Cody was given a final diagnosis of 1) left-branch pulmonary artery stenosis and 2) dilated cardiomyopathy of unknown etiology.

Cardiomyopathy is a disease of the heart muscle as opposed to the coronary arteries. In the dilated form of cardiomyopathy, the ventricles (one or both) become enlarged and exhibit a decrease in contractility. Clinical signs and symptoms of dilated cardiomyopathy include decreased exercise tolerance and dyspnea upon exertion. Failure to thrive in infants may be related to tachypnea with feeding, which can decrease nutritional intake. 7

At age 15 months, the results of tests for organic acids were again negative, and it was thought that there was no further testing that would explain his myocardial enlargement and hypotonia. In the meantime, the physical therapist documented that Cody exhibited diminished endurance to activity. At age 37 months, the cardiologist suspected Barth syndrome, and Cody was referred back to the geneticist. At that time, the level of 3-methylgluconic acid in his urine was elevated, confirming the diagnosis of Barth syndrome.

Numerous medical professionals have continually followed Cody since birth. At the age of 38 months, he attended a pediatric cardiology outreach clinic and received a working diagnosis of 1) Barth syndrome; 2) history of dilated cardiomyopathy, improved; 3) bicuspid aortic valve; 4) mild aortic insufficiency; and 5) atrial septal defect with associated right atrial and right ventricular enlargement.

With an atrial septal defect, the left-to-right shunt of blood allows oxygenated blood from the lungs to travel from the left atrium through the defect into the right atrium. 13,14 This results in enlargement (hypertrophy) of the right atrium, right ventricle, and pulmonary arteries. 13,14 At the pediatric cardiology clinic, it was noted that Cody had a 14-mm secundum atrial septal defect. The cardiology team discussed whether transcatheter closure or conventional surgical closure was the best option for correcting the defect. Because Cody was approximately three years, eight months old, he was within the recommended age range of two to four years for closure of atrial septal defects. 14 It was determined that the Amplatzer septal occluder (Agamedical, Inc, Minneapolis, Minn) was the most appropriate device for closure of the defect. 15,16 Use of this device to occlude atrial septal defects of the size presented by the subject is supported by the research of several authors. 15–17 Although use of the Amplatzer device and transcatheterization methods in general are accepted for treatment of many septal defects, this particular procedure was considered “compassionate” by the physician because it included a small residual fenestration in the device. This was included to prevent left ventricular failure should significant left ventricular dysfunction occur. The Amplatzer device was implanted, and Cody returned home two days later. This short hospital stay is common with the implantation of these devices using transcatheterization. 17,18 The prognosis for patients who undergo implantation of an Amplatzer device is good. 15–20 With little documented risk of endocarditis, thromboembolism, or device fracture, the Amplatzer device seems to be a successful alternative to more invasive surgical procedures. 18,20

Back to Top | Article Outline

Physical Therapy Examination

Cody was referred for an initial physical therapy examination at the age of 13 months. At that time a physical therapist, occupational therapist, and speech therapist examined Cody to assess his need and eligibility for early intervention services. Table 1 presents a summary of Cody’s gross motor abilities as measured by the Peabody Developmental Motor Scales (PDMS) at the initial examination. Cody demonstrated generalized weakness in the trunk and upper and lower extremities, and decreased muscle tone. At the time of initial examination, he could roll independently to either side, which was his primary means of locomotion. He could bear weight through his hands in a prone position and reach for objects. To attain and maintain a sitting or standing position, he required moderate assistance. Protective extension reflexes were delayed in sitting. Transitions to sitting from the prone position were absent. His head control in supported positions was good, but when those positions were challenged his head control was only fair. Cody preferred to play quietly, rolling from side to side to reach toys. Heart rate, respiratory rate, and blood pressure were normal. Cody found the pulse oximeter aversive, sometimes displaying negative emotional responses. Consequently, pulse oximetry was discontinued by the physical therapist. No edema was noted. With activity, skin color around the lips and under the nails was noted to be blue at times. Cody required long naps and sometimes fell asleep during an activity.

Table 1

Table 1

Back to Top | Article Outline


The original PDMS were administered to assess Cody for early intervention services. Although later in the study the second version of the PDMS was available, the original version was used throughout to aid test-retest validity. For infants and toddlers, a Z score of −1.5 or less is considered significant for educational planning purposes in the state in which he resided. Because Cody’s total Z score on the PDMS was −2.33, he qualified for services (Table 1). Early intervention services were started after the initial examination, as directed in the individual family service plan. He received physical therapy services once weekly in the home; each session lasted 30 minutes.

Back to Top | Article Outline

Intervention and Outcomes

Table 2 summarizes Cody’s gross motor development from age 13 months to 45 months. Physical therapy intervention focused on independent sitting, transfers (sit to side-sit and back to sit), four-point weight-bearing, improvement of postural control in sitting and standing, squat to stand with assistance, and improving overall endurance to exercise. Cardiovascular signs and symptoms in response to increased oxygen demands with activity were monitored throughout the 30-minute sessions.

Table 2

Table 2

At 23 months, his family moved to another state, and he began receiving physical therapy and education services through an education agency. Physical therapy services consisted of two 30- to 60-minute treatment sessions per month. Physical therapy intervention focused on facilitating quadruped creeping as well as standing with and without support, walking behind a push toy, side-lie to sit, and independent sitting. In hopes of improving progress, his mother sought additional weekly services for occupational therapy and physical therapy at a local hospital outpatient clinic when Cody was 27 months old. This added one additional physical therapy session per week to the two sessions per month he was receiving from the education agency. Physical therapy intervention in the medical outpatient program focused on improving endurance, walking independently, therapeutic play activities, transitional activities such as transferring from supine to sit, sit to four point and pulling to stand, and floor mobility.

At 27 months of age, cruising along furniture, supported walking, and playing in tall kneel and four-point were functional goals for Cody. He continued to demonstrate weakness in antigravity musculature and impaired postural control.

At approximately 30 months, Cody began receiving vitamin supplement shots at the suggestion of his physician. After this he had an improvement in appetite and alertness, and his willingness to interact during treatment sessions was noted to improve. At 31 months, Cody took two to three steps independently. At 32 months, Cody was ambulating with one hand held approximately 50 feet. At 33 months, he walked four feet without support. At 35 months, Cody was creeping on hands and knees independently. During this month he also independently started pulling to stand.

By 38 months, he was creeping up a step and sliding down backwards. Additionally, he accomplished independent sitting and walking. At 40 months of age, he was able to squat down and return to stand while holding onto a piece of furniture with one arm. He was also ambulating 15 to 20 feet independently with his arms in high guard. At 42 months of age, he was beginning to squat to stand independently without using furniture or assistance. Although Cody’s skills had improved markedly by this time, he still demonstrated signs of impaired cardiac functioning, including blue tinting around his lips and fingertips, a decrease in stamina and endurance, and a tendency to take 30- to 45-minute naps every two to three hours.

Before the transcatheterization, at 42 months of age, he was able to transfer from four-point to stand independently and walk distances up to 50 feet with his arms in medium to low guard. Independent navigation of the school hallway was not yet attained without loss of balance. He continued to demonstrate signs of impaired cardiac functioning. His PDMS total score placed him at the second percentile (Z score of −2.05) in gross motor skills (Table 1). His gross motor skills on the PDMS continued to improve, as demonstrated by the changes observed in his scaled score from 391 at 13 months to 447 at 42 months.

After the transcatheterization, upon his return home, Cody’s mother immediately noticed positive subjective changes. Cody exhibited an increase in energy level and alertness, as evidenced by a decrease in the number and length of naps and a corresponding increase in time engaged in activity between naps. He also demonstrated an increase in vocalizations as well as interpersonal interactions. Improvement in skin tone from dusky blue to pink and healthy was noted. The cyanotic tint around his lips and fingertips was also absent. These subjective changes can be explained by the physiological changes that followed implantation of the Amplatzer device. A decrease in cardiac work along with a corresponding decrease in pulmonary blood flow and subsequent reduction in the volumetric loading of the right side of the heart are examples of these changes. 19

Two months after the transcatheter procedure, Cody’s endurance had improved significantly, as demonstrated by his ability to independently walk 100 feet (Table 2). Impaired motor function was noted as Cody walked with arms in a medium guard position (Fig. 1) and by the inability to squat to the floor to pick up a toy and return to stand without the compensatory strategy of upper-extremity fixation (Fig. 2). He also continued to exhibit hypotonia, as demonstrated by sacral sitting and an open-mouth posture (Fig. 3).

Fig. 1

Fig. 1

Fig. 2

Fig. 2

Fig. 3

Fig. 3

Back to Top | Article Outline


Multiple aspects of care need to be considered when working with a child with a genetic syndrome that involves a cardiac defect and cardiomyopathy. Physical therapy plays a significant role in the outcomes and development of the child. The focus of the physical therapy program was on attainment of developmental milestones and functional outcomes while at the same time monitoring cardiovascular physiological status, improving motor function, and providing family education.

When working with a child with a known cardiomyopathy, the therapist must watch for signs of cardiorespiratory distress. Signs of distress include nasal flaring, bluing of the lips, increased respirations, and decreased activity tolerance.

In addition, neutropenia is often associated with Barth syndrome. Implications for therapists working with a child with neutropenia include being cognizant of exposing him or her to any illnesses. Patients with neutrophil counts lower than 500/μL have a significantly increased risk of infection. 21 As therapists work closely with their patients, it is recommended that they wear a mask if they themselves are ill (eg, have a common cold) to reduce the risk of infecting their patients. Therapists should also use sound hand-washing and toy-cleaning techniques.

According to the APTA Guide to Physical Therapy Practice, 22 Cody’s primary diagnostic classification is cardiovascular/pulmonary practice pattern 6D, “impaired aerobic capacity/endurance associated with cardiovascular pump dysfunction or failure.” Included within this practice pattern are ICD-9 codes for cardiomyopathy and secundum atrial septal defect. After implantation of the Amplatzer device and improvement in cardiac pump function, evidence of impaired neuromotor development remained, shifting the diagnostic classification to neuromuscular practice pattern 5C, “impaired motor function and sensory integrity associated with nonprogressive disorders of the central nervous system, congenital origin or acquired in infancy or childhood.”22 Cody will likely continue to receive services as long as he continues to make progress and possibly thereafter for maintenance of function.

The question arises of whether he would have made the same gains and be functioning at the same level he is now without physical therapy intervention. This question cannot be answered in a case report. Table 1, however, demonstrates an improved PDMS scaled score from 391 at 13 months to 456 at 45 months while programming was being provided. We propose that a relationship exists between his improvement and the intervention program, which included physical therapy. More importantly, Cody’s family reported that physical therapy has greatly improved Cody’s ease of performing daily activities, energy, confidence, and attitude toward participating in physical activity, play with other children, and social activities with adults and the family. Cody’s mother was very satisfied with the amount of participation she has been allowed in determining her son’s goals, the therapist’s respect for and interaction with her child, and overall physical therapy services.

Since the initiation of services at 13 months, Cody has made improvements in many areas. At the start of care he was not moving on his hands and knees to explore, pulling to stand, cruising along furniture, or moving up and down stairs. At completion of this study, he could do most of these activities independently and others with assistance. At 13 months, he was not performing any standing or walking activities, and at 45 months, he could do most with intermittent assistance and some independently.

Even after the placement of the Amplatzer septal occluder device, he continued to show significant delays in gross motor skills. It can only be hoped that the surgery will continue to maximize his endurance and cardiopulmonary function so that he will be able to keep up with his peers in play, and function as independently as possible within his environment.

Back to Top | Article Outline


The authors thank the family for their consent and support in the completion of this case report. Moon Jarvis thanks the South Dakota University Affiliated Program and Maternal Child Health Leadership in Educational Excellence for Neurodevelopmental Disabilities Program for support in additional pediatric interdisciplinary training and learning opportunities.

Back to Top | Article Outline


1. Kelley RI, Cheatham JP, Clark BJ, et al. X-linked dilated cardiomyopathy with neutropenia, growth retardation, and 3-methylglutaconic aciduria. J Pediatr. 1991; 119: 738–747.
2. Johns Hopkins University. Barth syndrome X-linked cardiomyopathy and neutropenia. Available at: Accessed September 1, 2000.
3. Barth PG, Wanders RJ, Vreken P. X-linked cardioskeletal myopathy and neutropenia (Barth syndrome)-MIM 302060. J Pediatr. 1999; 135: 273–276.
4. Cantlay AM, Shokrollahi K, Allen JT, et al. Genetic analysis of the G4.5 gene in families with suspected Barth syndrome. J Pediatr. 1999; 135: 311–315.
5. Orstavik KH, Orstavik RE, Naumova AK, et al. X chromosome inactivation in carriers of Barth syndrome. Am J Hum Genet. 1998; 63: 1457–1463.
6. Barth PG, Van den Bogert C, Bolhuis PA, et al. X-linked cardioskeletal myopathy and neutropenia (Barth syndrome): respiratory-chain abnormalities in cultured fibroblasts. J Inherit Metab Dis. 1996; 19: 157–160.
7. Towbin JA. Pediatric myocardial disease. Pediatr Clin North Am. 1999; 46: 289–312.
8. Long TM, Cintas HL. Handbook of Pediatric Physical Therapy. Baltimore, Md: Williams & Wilkins; 1995.
9. Marino BL, Lipshitz M. Temperament in infants and toddlers with cardiac disease. Pediatr Nurs. 1991; 17: 445–448.
10. Tomassoni T. Role of exercise in the management of cardiovascular disease in children and youth. Med Sci Sports Exerc. 1996; 28: 406–413.
11. Moore KL, Persaud TVN. The Developing Human: Clinically Oriented Embryology. 6th ed. Philadelphia, Pa: WB Saunders; 1998: 350–397.
12. Mosby’s Medical, Nursing, and Allied Health Dictionary. 4th ed.. St Louis, Mo: Mosby; 1994.
13. Moore KL, Dalley AF. Clinically Oriented Anatomy. 4th ed. Baltimore, Md: Lippincott Williams & Wilkins; 1999: 126–127.
14. Driscoll DJ. Left-to-right shunt lesions. Pediatr Clin North Am. 1999; 46: 355–368.
15. Formigari R, Santoro G, Rossetti L, et al. Comparison of three different atrial septal defect occlusion devices. Am J Cardiol. 1998; 82: 690–692.
16. Walsh KP, Tofeig M, Kitchiner D, et al. Comparison of the Sideris and Amplatzer septal occlusion devices. Am J Cardiol. 1999; 83: 933–936.
17. Radtke WAK, Waller BE, Shirali G, et al. Closure of single and multiple atrial communications using the Amplatzer septal occluder. Pediatrics. 1999; 104(Suppl): 665.
18. Masura J, Walsh KP, Gavora P, et al. Transcatheter closure of moderate to large sized patent ductus arteriosus using the new self expandable Amplatzer ductal occluder: initial clinical experience[abstract]. Circulation. 1997; 96(8 Suppl): I-373. Abstract 2087.
19. Pihkala J, Nykanen D, Freedom RM, et al. Interventional cardiac catheterization. Pediatr Clin North Am. 1999; 46: 441–464.
20. Masura J, Walsh KP, Gavora P, et al. Transcatheter closure of secundum atrial septal defects using the new nitinol self expandable, repositionable Amplatzer septal occluder: initial clinical experience [abstract]. Circulation. 1997; 96(8 Suppl): I-568. Abstract 3177.
21. Berliner N. Clinical disorders of neutrophils. In: Carpenter CJ, Griggs RC, Loscalzo J. Cecil Essentials of Medicine. 5th ed. Philadelphia, Pa: WB Saunders; 2001: 433–434.
22. APTA. Guide to Physical Therapy Practice. 2nd ed. Alexandria, Va: American Physical Therapy Association; 2001.

physical therapy; case report; X Chromosome/genetics; cardiomyopathy; congestive/genetics; muscular disease/genetics; neutropenia/genetics

© 2001 Lippincott Williams & Wilkins, Inc.