Ben Progressive peripheral and sensory neuropathy from age 4 to 9 (hearing, vision, ataxia, and muscle weakness).

Ben

Progressive peripheral and sensory neuropathy from age 4 to 9 (hearing, vision, ataxia, and muscle weakness).

Ben was a normal, active, boy with no past medical history until age 4 when his parents noted he seemed to be having difficulty hearing.  In preschool his teachers commented on his inquisitiveness, intelligence, and fun-loving (slightly mischievous) nature.  There was no history of congenital neurologic disease in either family, and the parents were not related to, or part of any genetic cohort.

Born in Boston after a normal pregnancy and normal term delivery (APGAR's at birth; 9 and 10), his only medical problem was a urinary tract infection at 3 weeks of age.  He was admitted to Boston's Children's Hospital for a urinary tract infection and accompanying fever to 104℉.  He was admitted and treated for 10 days with IV gentamicin and ampicillin with no complications. Gentamicin levels were followed and were normal.  Voiding cystourethrogram and renal ultrasound showed no genitourinary malformations.  Ben was followed by an experienced pediatrician at Children’s Hospital in Boston.  At age 3, Ben and his parents moved to Rochester, MN.  He was followed by pediatricians at Mayo Clinic.

At roughly 4 years of age Ben had an audiogram revealing bilateral sensorineural hearing loss most prominent in the low frequency range.  Tympanic membranes moved normally. An ENT exam of the ear was unremarkable.  Because his parents noted Ben sat close to the television and there was concern about his vision, he was seen by an experienced pediatric opthamologist.  Although it was not possible to test visual acuity, the ophthalmologist noted apparently normal refraction of the lens.  The optic disc was, however, slightly (1+) pale and there was a question of a slightly granular retina.  Photographs of the fundus confirmed a slightly pale disc and fine granular appearance to the retinal pigment epithelium.  Ben was able to identify numbers in color plates.  Otherwise, there was no nystagmus noted and his visual fields were normal.

Up until this time, Ben's parents felt that he had progressed normally with no difference in speech from other children.  He had learned his alphabet and could write his name.  However, they had noted that his gait seemed slightly ataxic but were not able to tell if this was new or that he just had not progressed as far as children his age.  He was referred to pediatric neurology.

Ben was fitted with hearing aids that partially corrected his hearing loss.  However, Ben's speech gradually became more nasal in quality with some deterioration in articulation.  He became progressively ataxic, and frequently fell.  He was no longer able to run because of his tendency to fall more frequently when running.  His strength has remained normal with no obvious loss of muscle mass.  However, he ‘hunched’ forward when standing in an apparent attempt to maintain balance.  He began to drool frequently, and put his shirt collar in his mouth to keep from having to constantly wipe is mouth.  He developed a tremor, particularly noticeable when he held a cup.  When reaching for objects he sometimes missed them by several inches.  His visual acuity was definitely not normal, although hard to quantitate. He read books avidly and watched television, etc. but could not always identify things at a distance.  His intellectual capacities were normal or above normal.  His outgoing personality made him popular, despite his inabilities.  Ben’s sister, one year younger than Ben, was normal with no medical problems.

At Mayo Clinic, the following laboratory tests were performed.  In summary, all were normal, except that creatine kinase was slightly low:

Serum Chemistry                                                                Hematology

Na                   141                   (135-145)                                  Hemoglobin    11.7      (11-14.5)

K                      4.4                    (3.7-5)                                      Hematocrit       35         (33-43)

Cl                     104                   (102-112)                                  Erythrocyte       4.41      (4.1-5.3)

Ca                   10.0                  (9.6-10.6)                                  MCV                79.3      (74-89)

Phos                 5.4                    (4.3-5.4)                                    MCH                26.5      (25-30)

Prot                  7.0                    (6.3-7.9)                                    MCHC             33.5      (32.5-35)

Glu                   77                     (70-100)                                    RBC Distbn       13.9      (12-14)

AlkPhos            318                   (340-570)                                 

GOT                 33                     (26-48)                                      Leukocytes       11.8      (4-12)

Bili,Total           0.3                    (.1-1.1)                                     Granulocytes   58.2      (25-68)

Bili,Direct          0.1                    (0-.3)                                        Lymphocytes   34.8      (30-60)

Uric Acid          4.4                    (2.5-4.4)                                    Mononuclear   7.         (4-11.8)

Creatinine        0.4                    (3.5-5.)                        

                                                                                                Platelets           377       (240-570)

Acid base balance                                                                 MPV                 7.6        (7-10.2)

Venous blood (8/21/89)

pH        7.32      (7.32-7.42)

pC02    50         (41-51)                                                  Urinalysis (8/21/89)

Bicarb  24         (21.3-24.8)                                                        Osm                 584

                                                                                                pH                    5.8

            Endocrine                                                                    glucose            negative

                                                                                                protein             negative

Thyroxine          7.         (5-12.5)                                                 microscopic     negative

TSH                   2.3        (0.4-7.0)

            Immunology                                                                Heavy metal screen (blood)

IgA       56         (26-232)                                                            Arsenic <.01

IgM      122       (47-200)                                                            Lead                <0.03

IgG      1020     (560-1307)                                                        Mercury           <.005

                                                                                                Cadmium        0.8        (<5)

                                                Other

Vitamin A                     363 ug/l                       Creatine kinase           45         (56-185)           

Vitamin E                     10.2      (5.5-17)             Lactate                        1.2        (.93-1.65)

RPR                              negative                      Phytanate                    0.0%     (0-.3)

a -Fetoprotein              18.8      (<15 for adults)                        CEA                 0.9        (0.0-5) 

Biotinidase                   9.5        (3.5-13.8)

β-glucosidase (WBC)               0.23      (.08-0.35)

α-galactosidase                       1.06      (0.6-3.63)

α -mannonsidase (T)                1.08      (0.71-5.92)

α -mannonsidase (WBC)          2.45      (1.5-3.33)

α -Iduronidase (WBC)              1.7        (.17-.54)

α -fucosidase (WBC)                1.0        (.49-1.76)------SEE FIBROBLAST CULTURE TEST

b-hexoaminidase                     10.9      (10.4-23.8) %A=80         (56-80% A is normal)

α -N-acetylglucos                     0.27      (0.09-0.58)

arylsulfatase A (WBC)              5.4        (2.5-8.4)

cereb. α galact (WBC)            62.9      (21.5-59.2)

Urinary screen for Inborn error- negative

Urine for oligosaccharides-negative

Urine amino acids-no abnormality found

Plasma organic acids-trace of butyric acid present/moderate amount of lactic acid (venous)

Quantitative plasma amino acids: no significant deviations from normal.

25 and 26 carbon saturated fatty acids were present in normal amounts. There was evidence of impaired formation of arachidonic acid.

Fibroblast culture sent to Ontario- no lactate/pyruvate metabolic defects.

Ben had radiological tests, audiometetry, and a nerve biopsy.  Bone age of the hand and wrist was normal for chronological age. Audiometric screening –age 4- 65 dB hearing loss bilaterally at 250 Hz. L sural nerve biopsy showed a neuropathic process characterized by slight reduction of fiber density, altered size distribution, and low grade axonal degeneration.  EM showed a neuropathic process with axonal degeneration and regeneration in both myelinated and unmyelinated fibers. Organelles in axoplasm and cytoplasm of Schwann cells are not specific to those seen in metabolic disorders.

Age 6

Spinal fluid: normal    

CSF                                          Clear

Total nuc. cells                         4/ul

Erythrocytes                             699/ul

Diff Cell count

            Neutrophils                  32%

            Lymphocytes               44%

            Monocytes                   22%

            Other                           2%

Protein                         25 mg/dl

Glucose                       52 mg/dl

CEA                             <0.2 ng/ml

IgG(CSF)                      1.78 mg/dl

Albumin                       12.6

IgG/Albumin                0.14

MRI Head  ‘MRI examination of the head is negative intracranially.  Special attention was paid to the hypothalamus and posterior fossa structures.  Note is made of a small amount of fluid or membrane thickening within right mastoid air cells.’

spine exam-prominent cervical lordosis. Cervical, thoracic, and lumbar spine otherwise normal

Muscle Biopsy  ‘The muscle fibers range from 18 to 45 um in diameter  (normal mean at age 6 is 28 um). Regenerating or necrotic fibers are not observed. Inflammatory changes are absent. Those fibers smaller than 20 um occur singly or in pairs. There is a mild increase in perimysial fibrous and fatty connective tissue. As adjudged by ATPase reacted sections, up to 12 type 1 fibers appear adjacent to each other in some fascicles. There is no grouping of the type 2 fibers. The rare atrophic fibers are of either histochemical type. Type 2 fibers have a slightly smaller mean diameter than the type 1 fibers. Ther are no unusual increases of acid phosphatase. Myophosphorylase reactivity is preserved. The muscle fiber lipid and glycogen contents are normal. Diagnosis:            1) possible denervation atrophy, slight  2) Type 2 atrophy, slight

Vestibular evaluation  Significant phase lead at .01,.08,.16,.32,and .64 Hz.

The normal gain and symmetry with abnormal phase demonstrated by rotary chair testing, suggested central vestibular dysfunction.

Deep tendon reflexes were absent at age 6. Plantar reflexes were extensor.

Pediatrician’s comment: ‘He is intelligent and friendly, speech is hard to understand and typical of deaf children.Wt 20.3 kg.(50th %). Ht  106 cm (<5th %). He can communicate with sign and speech.”

Ben progressively lost hearing and vision over the next 3 years. He became more ataxic.  Muscle mass progressively decreased, with increasing weakness both proximal and distal.  With growth spurts, weakness seemed to progress more rapidly. 

Ben was in a normal public school, assisted by a sign language specialist to participate in normal classroom activities.  He played soccer on a team with other boys his age, although he was not able to keep up with the other boys.  He took Tae Kwan Do classes and thoroughly enjoyed them, although his ataxia and weakness limited his abilities.  He read avidly, interacted well socially, and annoyed his sister with pranks. 

By age 9 it was clear that Ben would need a wheelchair.  One Saturday in October, after a normal morning reading and watching a favorite move (Dennis the Menace), Ben complained of trouble breathing (too weak to breathe).  He died within a few minutes in his parent’s and sister’s arms on the front porch. 

No autopsy was performed, but fibroblasts from an early biopsy were frozen and saved at -70℃ for future DNA testing. 

Ben’s sister grew up normally, and will graduate from college with a degree in Biochemistry in 2008.