Case Study XVIII

1. Case Study XVIII David Middaugh, SPT Doreen Ruiz, SPT

2. 6 month old Santiago • Full term • Uneventful birth • Typically developing until about 5 ½ months of age • Referred to PT for delay in age appropriate motor milestones

3. Examination1 • Mom reports: • Feeding difficulty/Vomiting • Seizures • Difficulty breathing • Continuous crying • Alberta Infant Motor Scale (AIMS) • Santi scored 17 • 10th percentile for age • Typical 6 month old • Score between 25-30 • 50th -75th percentile

4. Examination Cont.2 • During AIMS administration: • Irritable/ Hard to console • Abnormal breathing rhythm • Panting • Sighing • Jerky movements • “Wobbly” eyeballs

5. Neuro Exam3 • Generalized weakness • Low muscle tone • Primitive reflexes present: • Galant • Positive supporting • Negative supporting • Palmar grasp • ATNR

6. After initial evaluation, mitochondrial disorder is suspected Patient referred back to pediatrician

7. Diagnostic Tests4 • Muscle biopsy • Electron microscopy • useful to view the structure of the mitochondria, evaluate for accumulation of excessive mitochondria in the subsarcolemma region and evaluate for mitochondrial proliferation. • Skin biopsy • Test electron transport chain activity • MRI • Showed distinctive abnormalities in brain • Specific to brainstem and basal ganglia

8. Santi’s MRI Findings

9. Mitochondrial Disease5 • Malfunction of the energy-producing mitochondria found in all living cells • Hallmark characteristics: • “Common disease” with atypical features • More than one organ system involved • Recurrent setbacks or flare-ups from infection

10. http://www.mda.org/publications/images/q65mito1.gif

11. Mitochondrial vs. Nuclear DNA • Mitochondrial DNA mutation • Maternally inherited • All children will inherit • Heteroplasmy • Nuclear DNA mutation • Either parent can pass on mutation • More common but less known • Ø heteroplasmy

12. M.D. dx: Leigh Syndrome • Clinical presentation • Seizures • Vomiting • Difficulty breathing • Difficulty eating • Motor regression • Confirmed dx with: • MRI findings • Biopsies

13. Leigh Syndrome6 • Degenerative disorder of the central nervous • Can come from mitochondrial or nuclear DNA • Two major defects have been associated with Leigh: • Pyruvate dehydrogenase deficiency • Cytochrome c oxidase deficiency

14. Etiology1 • Respiratory chain enzyme defects • Complexes I, II, IV, and V. • Autosomal Recessive • inherited from genes from both mother and father • X-linked dominant • defect on the X chromosome and disease usually occurs in males only • Maternally inherited • from mother only • There may also be spontaneous cases which are not inherited at all.

15. Etiology continued7 • Research showed several different mutations leading to Leigh Syndrome • Most common in Complex I

16. Prevalence2,5 • Every 15 minutes, a child is born who will develop a mitochondrial disease by the age of 10. • Estimated that 1 per 40,000 births develop Leigh Syndrome • This figure would imply that about 100 new cases should be diagnosed each year in the USA.

17. NCMRR Model • Pathophysiology • Leigh Syndrome • Impairment • Decreased muscle tone • Functional Limitation • Can’t sit up and roll over • Disability • Can’t play with toys • Societal Limitation • Can’t interact with other kids and parents

18. APTA Practice Pattern8 • 5B: Impaired Neuromotor Development • ICD-9: 758 Chromosomal anomalies • 5E: Impaired Motor Function and Sensory Integrity Associated with Progressive Disorders of the Central Nervous System • 6B: Impaired Aerobic Capacity/Endurance Associated with Deconditioning • ICD-9: 333.0 Other degenerative diseases of the basil ganglia • 7A: Primary Prevention/Risk Reduction for Integumentary Disorders

19. Prognosis1,3,7,9,10,11 • THERE IS NO CURE FOR LEIGH SYNDROME • The prognosis for is POOR. • Individuals who lack mitochondrial complex IV activity and those with pyruvate dehydrogenase deficiency tend to have the worst prognosis and die within a few years • Depends on the severity of the defect • Individuals typically live anywhere from a few years to the mid-teens. • Those diagnosed with Leigh-like syndrome or who did not display symptoms until adulthood tend to live longer.

20. Goals • LTG: • Maintain skin integrity and mobility • Parent edu on progression of Leigh Syndrome • STG: • Parent edu on pt positioning for pt comfort in 1 week. • Pt will roll over (I) in 3 weeks. • Pt will increase AIMS score from 17 to 20 in 6 weeks.

21. Intervention • Multidisciplinary • PT • OT • RT • Hospice • PT specific treatment • Work on achieving age appropriate milestones • Maintain gross motor function • Positioning • Family education and support

22. Embedded Issue12 • Hospice Care • Provide medical, spiritual and psychological support • Caring for terminal infant • Coping with the loss of a child • Hospice care can reduce • Costs • Anxiety

23. QUESTIONS????

24. References • United Mitochrondrial Disease Foundation. http://www.umdf.org/site/c.dnJEKLNqFoG/b.3042173/k.6C37/Disease_Descriptions.htm#Leigh's • Thorburn, David. Leigh syndrome: clinical features and biochemical and DNA abnormalities. The Mitochondrial News, United Mitochondrial Disease Foundation. 1998; 47-51. • http://www.ninds.nih.gov/disorders/leighsdisease/leighsdisease.htm • Cohen, Bruce. Mitochondrial cytopathies: a primer mitochondrial cytopathies 2000. UMDF Conference. 2000;1-35. • MitoFIRST Handbook: An Introductory Guide. UMDF. http://www.umdf.org/atf/cf/%7B28038C4C-02EE-4AD0-9DB5-D23E9D9F4D45%7D/MITO%20FIRST.pdf • Bourgeois M, Goutieres F, Chretien D, Rustin P, Munnich A, Aicardi J. Deficiency in Complex II of the Respiratory Chain, Presenting as a Leukodystrophy in Two Sisters with Leigh Syndrome. Brain & Development. 1992;14(6):404-408 • Malfatti E, Bugiani M, Invernizzi F, et al. Novel mutations of ND genes in complex I deficiency associated with mitochondrial encephalopathy. Brain. 2007;130:1894-1904 • APTA. Guide to Physical Therapist Practice. 2nd ed. Phys Ther. 2001; 81:9-744

25. References cont. • Yasaki E, Saito Y, Nakano K, et al. Characteristics of Breathing Abnormality in Leigh and its Overlap Syndromes. Neuropediatrics. 2001;32(6):299-306 • Zhang Y, Yang YL, Sun F, et al. Clinical and molecular survey in 124 Chinese patients with Leigh or Leigh-like syndrome. Journal of Inheritable Metabolic Diseases. 2007;30:265 • Rahman S, Blok RB, Dahl HHM, et al. Leigh Syndrome: Clinical Features and biochemical and DNA Abnormalities. Annals of Neurology. 1996;39(3):343-351 • Frost M. The role of physical, occupational, and speech therapy in hospice: Patient Empowerment. American Journal of Hospice and Palliative Care. 2001;18(6):397-402 • Bénit P, Steffann J, Lebon S, et al. Genotyping microsatellite DNA markers at putative disease loci in inbred/multiplex families with respiratory chain complex I deficiency allows rapid identification of a novel nonsense mutation (IVS1nt-1) in the NDUFS4 gene in Leigh syndrome. Human Genetics. 2003;112:563-566 • Sudo A, Honzawa S, Nonaka I, Goto Y. Leigh syndrome caused by mitochondrial DNA G13513A mutation: frequency and clinical features in Japan. Journal of Human Genetics. 2004;49:92-96 • Hoefs SJG, Dieteren CEJ, Distelmair F, et al. NDUFA2 Complex I Mutation Leads to Leigh Disease. The American Journal of Human Genetics. 2008; 82: 1306-1315