American Journal of Medical Genetics 41:313-318 (1991)

Mucolipidosis wpe IV: Clinical Manifestations and Natural History

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David Chitayat, Catherine M. Meunier, Kathy A. Hodgkinson, Kenneth Silver, Michael Flanders, Ilse J. Anderson, John M. Little, David A.H. Whiteman, and Stirling Carpenter Department of Pediatrics, Division of Medical Genetics (D.C., C.M.M., KA.H.) , Division of Neurology (K.S.), and Division of Ophthalmology (MP., J.M.L.), The Montreal Childrens Hospital and Department of Neurology, Neurosurgery and Pathology (S.C.), The Montreal Neurological Institute; McGill University, Montreal, Quebec, Canada, and Department of Pediatrics (Z.A., D.A.H. W.), University of Connecticut School of Medicine, Farmington

The clinical manifestations and psychomotor development of five patients with mucolipido- sis IV (MLIV) from three Ashkenazi-Jewish families are reported. The presenting symp- toms were hypotonia, developmental delay, corneal clouding, and puffy eyelids. Four of the patients had convergent strabismus and none progressed beyond a developmental age of 15 months. One patient died of aspiration at 17 years while the oldest patient entered pu- berty at 20 years, developed a coarse face at 30 years, and is now 32 years old. Histopathologi- cal studies in four patients showed storage changes characteristic of MLIV.

KEY WORDS: Lysosomal storage, electron microscopy, skin biopsy, con- junctival biopsy, corneal cloudiness, developmental de- lay, Ashkenazi- Jewish, pig- mentary retinopathy, autoso- ma1 recessive inheritance.

INTRODUCTION Mucolipidosis IV (ML IV) is an autosomal recessive

lysosomal storage disorder characterized clinically by severe psychomotor retardation and corneal clouding [Amir et al., 19871. Most patients described are of Ash- kenazi-Jewish origin although the gene frequency in this population is unknown. Transmission electron mi- croscopic (TEM) studies show membrane-bound storage deposits in most tissues, including amniocytes and cho- rionic villi [Ornoy et al., 19871. The enzyme deficiency is

Received for publication August 31, 1990; revision received March 5, 1991.

Address reprint requests to Dr. D. Chitayat, Montreal Children’s Hospital, Division of Medical Genetics, 2300 “upper Street, Mon- treal, Quebec, H3H 1P3, Canada.

0 1991 Wiley-Liss, Inc.

still unknown, although ganglioside sialidase has been reported as a possible candidate [Bach et al., 19791.

We present five patients with ML IV ranging in age from 20 months to 32 years; the latter may be the oldest ML IV individual reported to date. All patients have been followed since birth and help illustrate the natural history and variability of this disease (Table I).

CLINICAL REPORTS Family A

The parents were of Ashkenazi-Polish origin, non- consanguinous, with an unremarkable family history. At the birth of their first son, the mother was 18 and the father 24 years old. In total they have had three affected and three normal children.

Patient 1. This young man was referred to our clinic at age 32 (Fig. 1). As a child he presented with hypotonia and strabismus, although head circumference (OFC) was normal. He sat unsteadily at 8 months and crawled at 1 year. In his second year he became spastic and head growth decreased. At 5 years he had rudimentary grasp- ing abilities, was unable to walk or talk, and had spastic quadriparesis, brisk deep tendon reflexes (DTRs), ankle clonus, tight heel cords, and bilateral Babinski signs. Pneumoencephalography documented cerebral atro- phy, more marked in the right frontal, left parietal, and left temporal lobes, although EEG was normal. He learned to sit alone at 7 years and could pull to a stand- ing position at 8 years. At the age of 12 he was institu- tionalized. Puberty began at 20 years without a recorded growth spurt. The cause of his problems was recognized at 24 years after his brother (patient 3) was diagnosed.

At 32 years he could not walk or sit alone and had difficulty chewing and swallowing. His height was 140.5 cm (<3rd centile), weight was 31.4 kg (<3rd centile), and OFC was 52.5 cm (3rd centile). He had a coarse face, minimal facial movement, a prognathous jaw, decayed dentition, and drooled constantly. His head was held in a hyperextended position, probably due to the bilateral ptosis first noted at 8 years (Fig. 1). He had roving eyes, nonreactive pupils, bilateral “ground glass” diffuse cor- neal clouding primarily at the epithelial level, clear lenses, white optic nerve heads, diffuse fine and coarse

314 Chitayat et al.

TABLE I. Phvsical Findings in Five Patients With MLIV*

Characteristics Sex Adverse pregnancy history Abnormal fetal movement Birth weight (%) percentile Recent OFC Hypotonia (noted at) Myopathic face Drykurly hair Short forehead Prominent supraorbital Ridges Puffy eyelids Ptosis Convergent strabismus (noted at) Pigmentary retinopathy Hypoplastic malar area Broad palatine ridges Hypoplastic thenar and hypothenar

“Tucked thumbs” Downturned corner of mouth Swallowing and chewing problems Incontinence

eminences

Patient 1 M

- 50 -2 SD + (6 month) + + + + + + + + + +

+ (10 month)

+ + + +

Patient 2 F -

- ND

+ (4 month) -2 SD

+ + + + + + + (16 month) ND ND ND ND

ND + + +

Patient 3 M + + 50 -2 SD + (3 month) + + + + + + +(4 month) + + + + + + + -

Patient 4 M

+ (?I 10 -2 SD + (4 month)

-

+ -

- + + - + (11 month) + + + -

- + + +

Patient 5 F - + 10-25 Mean +(8 month) + Coarse - + + + + (8 month) - + + -

a - + + +

* + , present; - , absent; ND, not documented. a Keeps hands “fisted” at rest.

pigmentation of the retina, and both cone and rod elec- troretinographic tracings were extinguished. He re- sponded to auditory stimulation and there was no organ- omegaly. He had clenched hands with ulnar deviation. Knee extension was limited to lo” and he had tight heel cords, equinovarus, and prominent acrocyanosis of the hands and feet. He has remained at or below a develop- mental age of 13 months.

Patient 2. This younger sister of patient 1 died of aspiration in an institution at 17 years (Fig. 2) and medical information about her was sparse, although her birth weight, height, and OFC were reported as normal. The mother recalled that although apparently less af- fected than her older brother (she could finger feed her- self a t 4 years), she had many of the same problems. Corneal clouding was progressive resulting in deterio- rating vision. Her developmental age remained at or below 12 months. A coarsening of her facial appearance was noted a year before her death, at which time she was prepubertal.

Patient3. This 9-year-old boy (Fig. 31, the youngest child of this family, was the product of a 36-week preg- nancy complicated by decreased fetal movements, breech presentation, and fetal distress resulting in an

emergency Cesarean section delivery. At birth he ap- peared normal and progressed well during his first 6 months; he smiled at 6 weeks, rolled over at 3 months, and followed 180” at 4 months. At 9 months, however, he could not hold his head when pulled to sit, slept poorly, was irritable, and would rhythmically bang his hands against his face, although he was alert and responded to his name. He could reach and grasp objects but could not transfer them hand to hand. He finger fed himself at 10 months. Generalised hypotonia was noted despite brisk tendon reflexes in both upper and lower limbs and flexor plantar responses. His lenses were clear and there was no photophobia, nystagmus, or strabismus. However he followed objects inconsistently and had bilateral diffuse corneal clouding, mainly in the epithelial layer which hampered clear visualization of the fundi. White optic nerve heads and attenuated retinal arterioles were seen and an extinguished electroretinographic tracing sug- gested widespread retinal degeneration. Plasma and urine amino acid chromatography, urinary mu- copolysaccharides and oligosaccharides, serum hex- osaminidase activity, brain CT scan, skeletal survey, EEG, and ECG were all normal. Nerve conduction studies showed some slowing of the motor nerve conduc-

Fig. 1. Patient 1 at 8 months (A), 13 months (B), and 32 years (C). Fig. 2. Patient 2 at 1 year (A), 11 years (B), and 14 years (C)

Mucolipidosis Qpe IV 315

Fig. 3. Patient 3 at 5 qonths (A), 2.5 years (B), and 9 years (C).

tion velocities. Skin biopsy showed findings consistent with a diagnosis of ML IV. At 2 years he could crawl, sit, and pull himself to stand. At 5 years, he developed pen- dular nystagmus with decreased tracking. He could walk with a spastic gait while supported and had bilat- eral hip adductor tenotomies. EEG studies showed mild disturbances of cerebral activity in the form of a poorly developed background for age, although lateralizing and epileptiform characteristics were not present. At 9 years (Fig. 3) his height was 110.5 cm (<3rd centile), weight 17.8 kg ( ~ 3 r d centile), and OFC 49 cm ((3rd centile). He was sociable and happy, could perform two step commands, and use some sign language. His geni- talia were normal and prepubertal. He had a flexion limitation of both knees, tight heel cords, and bilateral hammer toes. His motor skills have remained un- changed since the age of 4, and he has stayed below a developmental age of 15 months.

Family B The parents were Jewish, nonconsanguineous 27

years of age with an unremarkable family history. The father was of Hungarian descent and the mother was RomaniadLithuanian. Their first child was referred at 16 months. Since then they have had a second child and prenatal diagnosis (TEM studies of cultured am- niocytes) was normal. She has recently delivered an unaffected son. Patient 4. This 17-month-old boy was the product of

a term pregnancy. Birth length and OFC appeared nor- mal (measurements not known). Other than convergent strabismus, no abnormality was noted until 5 months, at which time he had not smiled, kept his fists clenched, and did not roll or lift his head from a prone position. At 11 months his weight was 9.21 kg (25th centile), length was 76 cm (75th centile), and OFC was 45 cm (25th centile). He smiled, had good ocular fixation, appeared to hear well, had better head control, and was more responsive. His anterior fontanelle was open and soft and his forehead was high with a ridge along the frontal metopic suture. He had single palmar creases and dim- ples on both elbows and over the metacarpophalangeal joints. Tone was mildly increased in the legs and vari- able in the arms. He had epithelial corneal clouding, which at 15 months had progressed resulting in deterio- rating vision. He developed pendular nystagmus. Mild diffuse disturbances of cerebral activity were noted on EEG with slow activity more obvious over the posterior head region. Hypodensity of white matter primarily in

Fig. 4. Patient 4 at 1 year.

the frontal region was noted on CT scan. ABR, EMG, NCV, liver function tests, blood gases, lactate pyruvate, serum, and urinary amino acids were normal. At 17 months (Fig. 41, length was 72.5 cm W5th centile), weight was 9 kg W5th centile), and OFC was 45.7 cm (<5th centile). He was still floppy and unable to sit or stand although could lift his head when prone. He would reach and grab small objects but was unable to feed himself and would frequently choke on his food. A photo- pic electroretinogram at 20 months suggested a slight delay of B-wave implicit time, normal amplitude, and morphology and ophthalmological exam showed mild temporal optic disc pallor and mottling of the retinal pigmented epithelium although poorly visualized though the cloudy cornease.

Family C The parents were of Ashkenazi-Polish origin, noncon-

sanguinous, with an unremarkable family history. They had one older unaffected daughter. Patient 5. This 3-year-old female, the product of an

unremarkable term pregnancy in which fetal move- ments were felt to be decreased, was referred to genetics at 8.5 months for corneal clouding, hypotonia, and possi- ble developmental delay. Esotropia had been noted at 3 months although concern was muted as her sister had the same problem.

She had trigonencephaly with a narrow bitemporal diameter (Fig. 5). There was a broad nasal bridge, bilat- eral epicanthic folds and esotropia, broad palatine ridges with a central ridge, prominent ears, bilateral clinodactyly of the fifth fingers, and partial cutaneous syndactyly of the 3rd and 4th toes. At 12 months, she could pull to stand, although she had unexplained screaming fits. Her vision was poor. At 16 months tone was increased, both centrally and peripherally, and epi- sodes of diarrhoea and vomiting were noted. Lactose intolerance was ruled out. At 18.5 months she could crawl and had crude grasping abilities. Five teeth had erupted. Flexion contractures of the knee, ankle, and heel joints were noted, all DTRs were brisk, and there was scissoring and hyperextension of the feet. At 24

316 Chitayat et al.

Fig. 5. Patient 5 at 15 months. Note the large, cupped ears.

months chewing and swallowing became difficult, and she was still unable to communicate. She has been esti- mated to function at a 6-7 month level. Her growth between 8.5 and 24 months has remained relatively stable, with weight and OFC at the 75th and 50th cen- tile, respectively. Her length has decreased from the 90th to the 50th centile.

Urine and serum amino and organic acids were nor- mal, and biochemical studies for possible storage disor- ders were all negative. MRI revealed partial agenesis of the corpus callosum with possible delayed myelination.

Histopathologic Findings Skin biopsies were performed on patients 1,2, and 3,

and results were similar. On semithin resin sections stained with paraphenvlene diamine and viewed * -

through phase optics (Fig. 61, numerous small dense " A u

granules were observed in the smooth muscle cells of the blood vessel walls and the erectors pilorum. These were also observed in Schwann cells, perineural cells, and interstitial cells of the dermis. Patient 1 showed an ex- cess of glycogen in many secretory cells that contained granular deposits. Despite his age, the quantity of stor- age in his skin structures was no greater than in the other patients.

Transmission electron microscopy showed that the dense granules were finely lamellar with a periodicity of 4.2 nm and arranged concentrically (Fig. 7). In patient 1, the lamellae of smooth muscle cells sometimes had a multitubular arrangement. In eccrine secretory cells, the vacuoles contained a variety of material: concentric lamellae, horseshoe shaped lamellae, and thin bundles of straight parallel lamellae, which had a transverse periodicity when tilted. Curvilinear and fingerprint profiles of the type associated with Batten disease were found in abundance in some eccrine secretory cells of patient 1, although rarely in patient 2 (Fig. 8).

Patient 5 had a conjunctival biopsy for TEM studies. Some of the epidermal cells, the vascular epithelium, macrophages, pericytes, and smooth muscle cells con- tained secondary lysosomes, laden with lamellated membrane and/or fibrillar structures.

DISCUSSION ML IV was first reported by Berman et al. U9741 and

most reported patients have been of Ashkenazi-Polish origin, although non-Jewish patients have been re- ported with essentially the same manifestations and course [Goutieres et al., 19791. Family B was of Hun- garian-Romanian-Lithuanian origin; thus the ML IV gene might be widespread in the Ashkenazi Jewish pop- ulation.

Although Dremancv histories in other reDorts have

Fig. 6. Semithin epoxy resin section, numerous dark granules (arrows) can be seen in the cytoplasm of eccrine duct cells. Paraphenylene diamine, phase optics. X 1,370.

Mucolipidosis Qpe IV 317

Fig. 7. Lamellae with a periodicity of 4.2 nm are visible at high magnification. x 100,000,

been uneventful, patients 3, 4, and 5 suggest possible prenatal manifestations of the disease. In patients 3 and 5 fetal movements were decreased, and in the former the presentation was breech. In patient 4, the patient had initial manifestations suggestive of decreased intra- uterine movements including a high forehead, de- pressed nasal bridge, epicanthic folds, hypoplastic malar areas, downturned corners of the mouth, single palmar creases, and dimples over the elbows and meta- carpophalangeal joints.

A review of 20 patients with ML IV LAmir et al., 19871 showed that most patients continued to acquire skills even at 3 years, although none developed beyond a devel- opmental age of 12-15 months. Visual, motor, and in-

tellectual abilities deteriorated in some patients not correlated with institutionalisation. In our series, pa- tient 4 has been in an infant stimulation program from 9 months of age and although new skills are evident, his vision is deteriorating. The motor skills of the other patients are limited although patient 3 can use some sign language. Whether this can be attributed to the infant stimulation program into which this child was placed we cannot tell.

The most evident eye finding is corneal clouding and in the summary by Amir [Amir et al., 1987],12 out of 20 patients had visual disturbances noted simultaneously. In six children the visual deficit was the presenting symptom. Nineteen out of twenty children had corneal

Fig. 8. Electron micrograph showing several vacuoles in the cytoplasm of an eccrine secretory cell from patient 2. Some of the lamellar bodies within them are loose and concentrically formed while others form straight or curved bands. x 16,750.

318 Chitayat et al.

opacities usually noted during infancy. In 13 cases, the corneal clouding remained static or increased; in only five cases did it improve. One 5-year-old child had re- duced vision due to severe myopia and retinal changes but no corneal opacities. In our series corneal clouding presented in infancy and in patients 3,4 , and 5, it was the most important diagnostic clue. Deterioration of vi- sion occurred in all our patients, associated with an increase in corneal cloudiness. All patients had normal lenses and patients 1,3, and 4 developed fundal changes and electroretinographic defects consistent with a pig- mentary retinopathy. All had puffy eyelids, a manifesta- tion not previously reported in association with ML IV. The abnormal storage material has been reported in both corneal and conjunctival epithelium and connec- tive tissue cells of the conjunctival stroma [Kenyon et al., 1979; Merin et al., 19751, as documented inpatient 5. The degree of optic nerve head pallor seen in patients 1 and 3 is more profound than one would expect if it was secondary to retinal degeneration from pigmentary reti- nopathy. This suggests that there is also a primary degenerative mechanism contributing to the optic atro- phy. The ptosis, myopathic face, gradual decline in facial movements, constant drooling, and difficulties in chew- ing and swallowing probably indicate an involvement of the cranial nerves, although hearing remains un- affected.

All patients were hypotonic during infancy with the gradual development of spastic quadriplegia in the 2nd year of life, and all (cf. patient 5) had a normal OFC at birth, postnatally developing microcephaly but no sei- zures. Growth retardation was evident in all reported patients over the age of 4, despite adequate food intake. The etiology of the failure to thrive is not known. All our patients had feeding difficulties, a feature not previ- ously emphasised, and patient 2 died of aspiration.

Coarsening of the facial appearance has not been pre- viously emphasised, although it was mentioned in a mild form in a 20-year-old patient reported by Riedel et al. [19851. It is possible that the coarse face, which de- velops in other lysosomal storage disorders, develops late in ML IV. Neither the previously reported patients, nor our patients had organomegaly.

Information regarding the pubertal development of ML IV patients is lacking since most reported cases have been prepubertal. In this series, patient 1 had delayed onset puberty and no associated growth spurt, while patient 2 was prepubertal at age 17.

Our skin biopsy findings are consistent with those previously reported [Crandall et al., 1982; Goebel et al., 1982; Kenyon et al., 19791. We wish to emphasize the prominent involvement of the inner cells of the straight portion of the eccrine ducts, which allows a presumptive diagnosis on semithin sections since these cells are rela- tively uninvolved in other storage disease. Electron mi- croscopy demonstrated concentric lamellar bodies in many cell types and vacuoles with a variety of contents in others, notably eccrine secretory cells. The presence of some inclusions of a type characteristic of Batten disease in eccrine secretory cells should not complicate

the diagnosis; they occasionally occur nonspecifically in this cell type [Carpenter, 19881. The enzyme defect caus- ing the accumulation of the storage compound is un- known. It has been proposed that the pathogenesis of this disease is a deficiency in gangliosides [Bach et al., 1979, Caimi et al., 19821, although recent reports indi- cate that its activity in ML IV is normal [Lieser et al., 19891.

The nonspecific initial clinical findings in ML IV and the lack of a noninvasive, specific laboratory test proba- bly accounts for the delay in diagnosing this disease. Patients 1 and 2 were diagnosed as having cerebral palsy, although the corneal cloudiness did not fit this diagnosis. Once institutionalised, the diagnostic inter- est in these patients declines so that a correct diagnosis for genetic counselling may never be made. ML IV should be considered in infants of Ashkenazi-Jewish origin presenting with developmental delay and found to have abnormalities in tone and corneal clouding.

The increasing number of patients diagnosed among the Ashkenazi-Jewish population suggests a relatively high frequency of the gene in this population. ML IV, unlike Tay-Sachs disease, has a protracted course so that the occurrence of an affected child has long-term implications. It is important therefore to identify such patients through chronic care institutions and eye clinics in areas where large Ashkenazi-Jewish commu- nities reside.

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